It's about as different as the B-sides are in RE2 Remake, maybe even a little less so. It's also restricted to the higher difficulties. I found it pretty meh overall. Doesn't really add much to the replayability.
@development: The esaiest answer is no, the main quest items are always in the same places. The events always happen exactly the same and in the same order. The puzzle solutions are always the same. In RE2, the 2nd runs changed up the front a bit and some of the puzzle solutions (maybe all of the actual puzzles that required inputs). I can tell you there is nothing like that in RE3, as I have the platinum trophy.
If you've ever played a Capcom game with difficulty levels before, you know that they do three things: 1) Introduce end game "minions" earlier (minions being enemies you see outside of boss fights) 2) Enemies take more damage 3) There are less items for you to find and use. These are the only things that change, and I don't think that's a spoiler, considering that every Capcom game with difficulty levels works that way.
@development: I had a lot of fun with RE3. I have also been having a lot of fun with Resident Evil Resistance (which comes with RE3). I didn't think the asymmetrical multiplayer RER would entice me. I tried it, and keep going back. Right now, I'm maining a girl (I can't remember her name), who gets an ability where for a limited time, she can fire infinite ammo. So, a fully automatic AR or a rocket launcher lets me just go off on people.
If it interests you, I would pick it up when it goes on sale.
@shindig: No, no choices whether to run or fight, really the entire mechanic of Nemesis chasing you around like Mr. X is only in the beginning of the game, after that it because as straightforward/linear as RE5 and 6 more or less for most of the rest of the game.