My primary Homebrew is nearly 40, and has been 'rebooted' several times (and due to time travel mechanics, they're all in continuity, despite the evolution between each reboot).
Sphereworld was a lesser success. It was used for two different campaigns, but the 'Alice in Wonderland' feel of it made it suitable for a smaller audience.
I'm running a game that is based out of an interdimensional mansion that allows the PCs to travel to any setting - so there has been a combination of homebrew and established setting ... I look at it as a sampler plate.
I ran a campaign that is sort of Homebrew. It took place in the 'real world', except in 1867 magic 'returns' to the real world, awakening sleeping monsters, opening portals to other worlds, and changing the path of the world. It started in the West of the United States, and went really weird. I have a new version of this campaign lock and loaded to run that instead starts in London and uses unique mechanics based upon 4E D&D with different unexplained mechanics for each PC.
I've run dozens of 'adventures' spanning 10 to 20 sessions that took place in nondescript settings. I shaped the world around what the PCs wanted to do. For example, I let a cleric make up a God or pick one from any setting.