I typically use the Spinward Marches circa 1110 as a go to setting, because:
a) I like it -- it's got variety (hi tech developed worlds, low tech backwaters, military and political intrigue, a frontier to explore, and the spinward main.
b) It's easy for one-shots -- Traveller is an alternate game to "try out" for most people I game with, so the ready made setting is convenient
c) I know it well -- this makes it easy to improvise things, like travelling to worlds I have little or no prep for during one-shots.
I have made original settings though. These include a future earth setting, where a Terran Empire has splintered, and numerous successor states are reforming. I set mine in a no-man's land between two larger states, filled with independent worlds, and many client states, including some alien races, who are playing to the two powers off each other, while attempting to maintain their independence.
I've also done a lot of mini-campaigns in limited settings, including: a short campaign on a prison planet, a campaign centered on marooned colonists trying to escape from a "death world", TL9-10 traders plying the sublight spaceways in a Jovian system, a star trek style exploration mission "beyond the frontier", a military wargame where the players made naval crew running a cruiser, and military crew to play when conducting a landing operation, and PCs on a 21st century earth exploration ship to Alpha Centauri waking up centuries past their arrival date, and exploring strange 2001 A Space Odyssey type phenomena.