I've noticed that on my guitar, the F note on the E string (sixth string) sound almost like flat.
That's a real problem, specially when I'm doing two fingers power chords.
The saddle is set correctly and the string plays a perfect E note on the 12th fret.
All the other strings around the fretboard sound much better than the E string.
Any ideas?

I'm playing an Epiphone Les Paul Standard with Elixir .009-.042

Erm, in no ways am i an expert, just what I've heard from various people:
your frets might be at the wrong height (which means they can be levelled [v expensive])
Your truss rod might be messed up
Your trem system might be unbalanced for that string.

Does it play the harmonic on 12 AND the note on 12 fairly precisely the same? and is that tuning by ear or tuning with a tuner? (and how far is it out then)
Is it a recent problem? When was the last time you changed strings? have you changed gauge? Did you do a full "service" when you did (checking action/intonation etc.)

It sounds like your intonation is off which can be for many reasons such as misaligned bridge, misaligned nut, misadjusted truss, misaligned frets, warped neck etc. ( in rough order of whats least of a bugger to fix).

Depending on the problem either take it to a shop where it may be embarrassingly fixed in minutes (or may need a whole load of work) or attempt it yourself if you know what you're doing
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To me it sounds like an intonation problem, im sure there are guides online to do it yourself. A simple bridge adjustment is REALLY simple to do so theres no point in taking it to a tech if its thats the case.

Obviously there ARE other things that can cause that problem, but check if u can sort it out by altering the bridge
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Also, A trick that you can try is not to get it to sound correctly at the 12th fret, but try the 15th fret. I'm not talking about making the 15th fret sound an e, but a g. That will also help.
you guys are drunk when i thought i was the one...
if i understand you right, your intonation and all other bullcrap which is basically the same is set right, then its very simple: because of the fat string your first fret doesnt sound right on the e string (happens a lot on cheaper guitars) but as long as it sounds flat you can always bend it in a little. just grab the f a little harder.
pretty weird for a first fret to be flat. maybe raise the action a little.
and put on some fatter strings - fatter strings solve everything.
Quote by ruletheneck
pretty weird for a first fret to be flat. maybe raise the action a little.
and put on some fatter strings - fatter strings solve everything.

As someone else said, could be a cheap guitar issue.

Also, E-F is a half step, is that what you mean by it being "flat?" Not trying to sound like a dick, can just never rule these things out