MegaTokyo is set in Japan, but it's "Original English Manga", i.e. it's not translated from Japanese, and you read the book from left to right (and front to back) rather than the opposite way round. I've read a bit of Japanese manga, and seen some of their anime, but not a huge amount. One of the things that puts me off a lot of it is the amount of exaggeration involved; it's as if the characters don't have a volume control, so all of their emotions are at maximum intensity all the time. By contrast, some of the art in MegaTokyo is a bit more subtle. For instance, look at the final panel in strips 375 and 379: Kimiko's mouth is almost a straight line, but I'd describe it as a gentle smile.
Having said that, the comic does have its fair share of outlandish elements. I've always liked comics/cartoons where someone has a moral dilemma and they get little angels/demons popping up on each shoulder to advise them. (Sluggy Freelance has done this a few times.) In MegaTokyo, the "angels" work for the CEA: that's the Conscience Enforcement Authority. One of my favourite items of clothing is a CEA hoodie; it says "XXS" on it, to reflect the idea that it's supposed to be worn by someone who's only a few inches tall.
Reading through the books, I think the funniest strip was 347 ("Oh look, more bombs"). It might help to read from 344 to 349 to get the context.
There's an odd time dilation effect in the series, since time passes much more quickly for us than it does for the characters. This becomes much more obvious when you read several strips at once. For instance, Piro gives Kimiko his rail card in strip 62 (03-Jan-2001). Erika and Kimiko then discuss this in strip 135 (20-Jun-2001), where Erika says: "You bring it up at least once a week." These strips were several months apart in real time, but only a few days had passed in comic time. This is confirmed by the timeline printed at the back of book 5: Piro gave Kimiko the card on Thursday (day 49), and she discussed it with Erika the following Monday (day 53). More generally, the comic has been running for 10 years, so it feels as though it's taking a long time for relationships to develop. However, the main characters have only known each other for a couple of weeks, so it's really more of a whirlwind romance.
Looking at the early strips, some things do seem a bit contrived. In particular, there's a bit of a "small world" syndrome, where Piro and Largo keep bumping into Erika and Kimiko. I've never been to Tokyo, but I gather that quite a few people live there! It also took me a while to tell the female characters apart, but I got the hang of it, mainly by looking at their hairstyles.
On a more positive note, the main characters all have interesting flaws. I don't like the term "Mary Sue", because it's been overloaded to mean so many different things that it's now basically meaningless. However, one aspect of that is "self insertion", i.e. an author putting themselves into a story. (This happens a lot in poorly written fanfic.) In the case of MegaTokyo, the two main male characters (Piro and Largo) have the same nicknames as the guys who created the strip. However, strip 385 shows that Piro (the character) lacks self-awareness, and Fred Gallagher (the writer/artist) is obviously doing that deliberately.
The books reprint the strips from the website, but they also have some original stories. I'm not sure of the terminology, but these often involve the MegaTokyo cast put into a different context. On Star Trek: The Next Generation, the crew would sometimes go off to the holodeck, e.g. for a Sherlock Holmes adventure. When they did that, they weren't simply reading out lines from a novel; it was more of a roleplay thing. Now, imagine that the TNG crew did a holodeck episode like that, but it was based on a plotline from Buffy. If you've never seen Buffy, you'd probably have trouble following it, particularly if the crew kept referring to each other by their normal names, i.e. only the personalities would be different. In the MegaTokyo books, I assume that the bonus stories are based on other manga/anime, but I don't recognise them, so most of it goes over my head. For instance, I've heard of "Full Metal Panic", and "Full Megatokyo Panic" is presumably based on that, but I've never seen/read it.
To a lesser extent, this is also an issue with the main storyline. For instance, one strip (where a character gets hit by a bus) only made sense after I saw an episode of Excel Saga. However, it's less of a problem there, and I still like the comics even if I'm missing a lot of the references.
The first strip after book 6 is 1270 (05-Jun-2010). There were 5 strips in June, 4 in July, 3 in August, and 3 so far in September. In particular, the current conversation started in strip 1274 (30-Jun-2010). Reading it out load, I'd say that it's taken about 9 minutes in comic time, but almost 3 months in real time. So, that makes it quite hard to keep track of the context, unless you keep re-reading the previous strips. Right now, the whole thing is fresh in my mind, so I understood the latest strip (posted today). When I start to lose track of it again, I think I'll unsubscribe from the RSS feed, then just wait for the next book to come out.
The X-Axis review of Megatokyo vol 1
Something Positive's parody of "Sad Girl in Snow"