The following is a list of the unecessarry deviations from the Dungeons & Dragons rules made by Obsidian. This does not include deviations which were necessarry to adapt the game to the PC...
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The "Mitchell Brothers" resurrection system. - NWN2 will grant your characters complete and utter immortality. Death is merely a temporary inconvenience and all party members will be revived at the end of a fight (or even during combat if the implementation is anything like KOTOR2). Like the aforementioned game, all joy will be sapped from the (probably endless) combat sections, by the fact that it will be impossible to die. No strategy will be necessary as you will be able to spam your way through any fights.
You will never be able to say "we lost a lot of friends on the way, but we finally made it," or "I never liked that guy, let's leave him to rot." You will not even be asked if you want to resurrect your characters, never mind receive a gold or xp penalty. Raise Dead and Resurrection will be made completely irrelevant, which will likely lead to further disregard for the rules in attempt to balance this out. And so we take another step on the road to a magic system that contains only direct damage spells and buffs.

Merging of Knowledge skills into "lore" - The idea that all knowledge is summed up in one skill is completely ridiculous: better to separate it from the rules altogether. I'm not asking for every type of knowledge skill, but a selection of three or four could have worked. With synergy bonuses, they could have been quite powerful. They could have been used to examine creatures, track, identify different types of item, aid in crafting items, as well as in dialogue. If that wasn't enough, you can just make the DCs lower so that one rank counts for a lot more.
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Inability to equip non-proficient items - again, limiting this adds nothing to the game. Is it not reasonable that sometimes characters might have choose to use items they might otherwise not? Perhaps to take advantage of magical effects or damage certain creatures? So we loose the ability to put players in interesting situations. If you're worried about new players, just add a pop up box saying "your character is not proficient with this item and will suffer a penalty to hit" with another box to "never show this message again." The new players argument is invalid and this only subtracts from the game experience.
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Petrification - Petrification is permanent by definition. I have no problem with weighing the dice in the players favour with the difficulty slider, but to say something is temporary when it is not is just blatant disregard for the spirit of the rules. How many plots would be spoiled if that ancient wizard had walked off five minutes later, instead of standing forgotten in the desert for untold millennia? If you really want people to be able to chicken out of this, they make a separate rules slider which is independent of difficulty, so that players can have a chance without needing to mangle the rules in the process.
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32 point buy. For some reason (which I remain forever unable to comprehend) point buy has been increased to 32, the maximum allowable under 3.5 rules. Presumably to make the game more "epic." Every kind of interesting character is possible with 25 point buy: the all-rounder cleric, the intelligent but frail wizard. All that this ability point gluttony actually serves to accomplish is to make it completely unnecessary to have any weak or even average stats, so that all characters are superior to normal people in every way. If you want to make the game easier, just lower the ability scores of everyone else; it's all completely relative anyway. So what are you actually achieving, other than distorting the game? I am fairly certain that this will merely lead to all enemies being scaled up too, ruining any sense of proportion (or perhaps they'll just make the game ridiculously easy like KOTOR2?).
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Always Max Hit Points - No longer is this tied to game difficulty. All characters will now receive max hit points per level. The whole point of the random hp on level up is to enforce the idea that hp is not proportional to level: 2 level 1 characters are supposed to be more powerful than 1 level 2. Get rid of the randomness if you want, but anything but the max. What's wrong with the average rounded up/ down? Or any other approach? Or a selection of options? Again, it's all completely relative. Just make the enemies weaker (or more accurately, bring them back down to where they should be by the rules). I can't think of any other approach that would have been worse than the one they have taken.
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Up to level 20 in a single campaign - It takes characters like Drizzt a lifetime of adventuring to reach level 14, and they propose to take us to the maximum allowed in the standard rules in a single campaign. If you do the maths, it works out approximately 5 times as fast as Baldur's Gate. Now I'm prepared to compromise, but that's just ridiculous. It's even faster than nwn, which was unanimously agreed to be too fast anyway.​

I also dislike the Parry/Discipline/Knockdown trifecta and I wish we had dealt with changing it over to the proper rules a long time ago.

The companion death rules and advancement rate are for our Official Campaign only. The former is scripted and the latter is simply how we chose to give out XP. Raise Dead/Res. are not irrelevant in the OC; I use them regularly to bring back allies in combat. A wipe is still a wipe.

I completely disagree on knowledge skills. I think the "find out what skills are worthless by playing the game!" approach contributes nothing to anyone's experience. Even in pen and paper sessions, DMs often have to stretch to allow players to make use of their various knowledge skills.

The ability to equip items with which the character is non-proficient is something I talked to the programmers about. The effects would have to be coded or scripted and we had time for neither, unfortunately. I also agree that it should be allowed with a warning.
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The choice to revive companions after combat automatically was made very early in the project and many aspects of the OC rely upon it.
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This is not my design. It is not my story. It is a choice that I inherited from the original lead designer, so I can only explain that it is integral to how the campaign functions but not to how the game itself functions. I'm not going to defend it because it isn't a choice I would have made.

If I were making my own campaign, people would drop like stones, you'd have a level cap of eight, and no prestige classes.​