As someone who has lived here long enough to not attribute being unable to make friends, it is very much a case of being a fish out of water, or a square peg trying to fit into a round hole.
I have narrowed it down to several factors (and note, these aren't meant as criticisms, but observations):
1) Americans seem to tend to socialise less with co-workers outside of work. This could be partly due to the greater distances that people generally commute. There seems to be more of a general reluctance to acquire new friends as many people are content with their existing circles / cliques. Having to work longer hours would also hinder any time to spend with friends.
2) The US is a much more materialistic society, so you stand a greater chance of being judged based on your house, car, physical appearance or how much you earn.
3) Aside from the west coast where many people seem more open to deviations from the norm, many more people here seem to follow the plan, doing X by Y age (graduate high school > go to college > graduate > marry college / high school sweetheart > buy house in suburbs > breed). Any deviations seem to be frowned upon by many people who deem such people who didn't follow the plan as "losers".
4) Americans seem to be more achievement / goal oriented. To a Brit who is also that way, the US would seem better, but not all of us are wired to be competitive. Many Americans also discuss their college days a lot.
5) American humour is very different. I don't think they find our self-deprecating, more dry humour as funny, though some do, hence the popularity of some British comedy shows over here that have a cult following. I only really find the black comedians funny here + the late George Carlin. I miss the banter that British people engage in, not being afraid to take the piss, even out of themselves. That doesn't seem to fly well here.
6) Sports. Any hardcore British football fan may have a hard time here. The MLS has grown and does have a huge following, but it's not quite the same crowd that you'd get at a Wolves or Stoke City Saturday afternoon match. To talk sports, you've really got to be prepared to get into an American sport. I just find the whole sport thing to be very different.
7) Politics. The right-wing here are very alien to me and seem far more nutty and extreme than the average British Tory voter, who I could still have a sensible discussion with, even if we disagreed on many issues. The right wing here seem so brainwashed, loud mouthed, nutty and obsessed with issues such as abortion and same sex marriage.
Obsession with physical appearance. Lots of teeth whitening, Botox, breast enhancements, magic pills for weight loss, plastic / cosmetic surgery, general obsession with wanting to not age. It's as if many people want to be "perfect" and never age. I find the whole thing very alien.
9) I do not agree with many attitudes towards the poor, those who are weak in any way, blaming them for their problems to the extreme. We know some people are poor because they ****ed up, but you cannot apply that to all. I am very much at odds with the whole "individualist" "pull yourself up by your bootstraps" mindset.
10) A very different attitude towards the role of government.
11) Lastly, I have always been uncomfortable with people's tendencies to pry here by asking about your job, where you went to school and even your salary. As a British person, I find many of the questions to be "off limits".
In summary, I just feel like it's harder to be different here. People are usually nice and polite enough on the surface, they're not as reserved, but there's just something missing, at least for me.
I hope that explains it.