Recalling my first time playing it...
Easy: Del Lago, Salazar, Bitorez and Dr. Salvador (and even he killed me about 3 times outside Bitorez's house)
Hard: Everything else... LOL
The thing is, I played RE4 before any othe RE title, not knowing anything but the vague idea the movies give...
I had just bougth a PS3 and never played anything but Mario&friends, so the transition between a game were you just stomp enemies into one where you have to blast their head off was made rather harshly...
I must say I've never enjoyed a game the same way I did with RE4...
I also must say that it took 25 and a half hours to finish it the 1st time...
I must say too, I didn't found out until the 2nd round that you could upgrade your weapons beyond just changing them for other models...