I would have to say I have two MTUs that I play in: one is my take on the OTU, and the other is my homebrew. Like others here, I started playing back in the days before the 3I setting was much more than a twinkle in MWM's eye.
When I play in the 3I setting, I play it pretty much straight up as written, with a small-ship universe slant (big ships exist; when you see one, it means big trouble). Virtually all my 3I games have been set in and around the Marches, Classic-Era, though Gateway is certainly tempting.
Now, the Exile Clusters, my homebrew, is another matter entirely. The original version I've used for 25+ years is a sector-sized area containing a number of polities and many, many "independent" worlds. It's called the Exile Clusters because humanity came to the area via a one-shot wormhole several centuries ago; the exact reasons why are lost to history, as the refugees scrambled to establish colonies and simply survive at first. Eventually, most of the colonies more-or-less prospered and there have been subsequent waves of colonization. Some of the daughter colonies have done well enough to spawn colonies of their own. A few of the original ones were lost, and there are disputes about just where they were, anyway... cue the Indiana Jones music!
The area was already home to several alien races, who get along variously with the humans. Actually, in most cases I lifted many alien races from Traveller, worked up a different history for them, and dropped them in. The K'Kree became the Big Bad, just nudging into the rim-spinward edges of the region. The Vargr kept their Terran canine uplift heritage but came along with the humans. The Droyne & Hivers stayed on as indigenous locals, along with the Virushi and some others. The Zhodani became a human subculture that came through with the rest of their kindred and founded their own colony, and formed a distinct polity.
The largest polity, the Decatur Unity, used to be the sort "feudal technocracy" that was all the rage back in the 1980s... and then I read the Afterword section of the final Sten book, where Cole & Bunch rant about SF authors and their persistent fascination with monarchies. I found myself agreeing with them and the Unity has since morphed into a federation. The core members of the Unity are 5 of the original human colonies and many of their daughter colonies. The Unity has a stated goal of uniting all the human worlds and allying with the local alien races to stand against what seems to be an inevitable conflict with the K'Kree. Naturally, people being people, not all the sophonts around are on board with this program.
The Exile Clusters are meant to be small-ship friendly. I've tweaked the commerce rules to make things distance-based rather than per-jump, dropped the cost of life support and at various times played with cutting jump fuel requirements to 10% of the rules (i.e. 1% per parsec instead of 10%). Sigg posted some really nifty rules a couple of years ago for up-gunning small ships, adapting some concepts from HG2 to Book 2, that I really really liked and have incorporated. They allow one to differentiate between a dedicated military vessel and an armed merchie in the small ship realm in a pretty clean fashion.
Big ships do exist, to a point, but almost no one can afford anything really big. The Unity has a bunch of 4 kDton "patrol frigates" that roam around the independent worlds outside the Unity proper, and often visit smaller polities; they do pirate suppression, show-the-flag, S&R, all that sort of thing. The Unity and a handful of the biggest polities have some larger ships but not many; there have been a few sizeable wars fought in the region, but nothing really big for the last 20 years or so aside from some initial clashes with the K'Kree.
As far as rule mechanics go, I'm a CT/MT kind of guy. Generally I use MT for character generation, though for the most recent games I ran two years ago I adapted Don McKinney's point-based system to accommodate the wishes of my players, who were largely really opposed to purely random chargen. For tasks I've used different things at different times, from straight CT to MT to CT with the BITS system bolted on. I've been looking hard at the UGM lately may supplant the BITS system with that. Combat has floated too, from CT to AHL to MT, going back to AHL. I do own ACQ and may work that in some day.
Hm, other areas of divergence... some nanotech and cybertech around, as well as some advanced biotech; began adding these in my Shadowrun days. Psionics outside the Zhodani area are rare and generally don't come up in games. Anagathics as written don't exist, though people definitely pursue life extension technologies.
Current max TL is D, in the Unity and a couple other places.