ikdind said:
In my head, I've always pronounced it "ee-six-twenty-one", or "ee-six" for short. I'd also accept "the only furry booru that matters".

Eh this, pretty much, seems simplest and straightforward.

CCoyote said:
I pronounce it E-six-two-one. I don't know if there's any official pronunciation. Trying to dictate that might go over about as well as telling people that .gif is pronounced with a J.

I suppose I am one of the rare few who spells out the acronym, heh.