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Realistically, I've never thought swords could do very well versus guns, but Sephiroth's fast enough to dodge until Ol' Albert needs to reload, and then he's toast.

And by toast, I mean shishkabob.

Ah, but fist-fighting against Masamune? Psssht.

Masamune's got a six-foot reach that Wesker can't get into, if Sephiroth is fast enough...

...though if we're talking hand-to-hand combat, no weapons, no magic, I'd say it would be a pretty close bout.

Simple bullets against our Lord. Don't be silly.
Even if Wesker takes cover, don't forget, the holy sword of God can cut through buildings.

But, Wesker can dodge literally ANY attack, I mean ANY attack, getting the heart of Africa was a b***h, cause you had to catch him off guard, and if he's fighting someone as powerful as Sephiroth, I'd say he'd keep on his guard, so that does away with Sephy's sword. Then hand to hand, Wesker has ungodly like strength and can use the virus to his advantage to multiply his already incredible strength, also adding the 'dodge any attack thing' gives him a huge attack advantage over Sephiroth, really the only chance Sephy would have against Wesker is using a large attack such as Meteor. All in all, I love Sephy, but in a fight with no magic, and possibly even with Sephy using his sword, for which you have to account for Wesker's guns, Wesker would win.

There are some holes there though, who remembers Wesker EVER running out of bullets? Hm? Yeah, and remember, RE5 wasn't Wesker's first appearance, I do believe there was a part in one of the earlier games when someone attempted to stab him, and the metal just bent, didn't even penetrate his skin. Then, after using the full effect of the virus, it took two v354-x10 model rockets to take him down, those rockets are like miniature atom bombs. Then with the magic comes the dodging capabilities, the only magic Sephiroth COULD use and actually hit Wesker would be meteor, in which he would also destroy him self. Then there's Wesker's strength, in Before Crisis, Cloud was impaled by the masamune and still managed to live and fight Sephiroth, considering that we can all agree that Cloud has the physical prowess of a small lemur, I'm pretty sure Wesker could stand a few hits, along with the fact that he's invincible, the man swam through lava without even so much as a little burn mark. He can also read his opponent's movements. I truly hate this fact, but in a fight between Sephiroth and Wesker, Sephy's screwed.

Okay, well Albert Wesker is infected with the virus but takes a serum to keep it in check. He can still use the abilities though, i.e. strength, speed, invincibility. His offense does mainly consist of guns and fist fighting, but his physical strikes could be considered bullets. I'd take a gun over a sword any day, but anyway, at the end of the game the virus gets to "uppity" before he gets the chance to inject the serum and he turns into a kick a** version of a tank from L4D, cept ALOT bigger, with a tentacle that can stretch to unkown lengths, this adds to his strength, and after this point he obtains to odd ability to open portals from the ground that release laser like beams. I do truly have to say that Wesker is more powerful.