Hmmm...somehow, I forgot Torg. Plus, a Gamma World/AD&D fusion- especially using stuff from “S3: Expedition to the Barrier Peaks” would actually work pretty well.
But if I wasn’t going to use HERO to do something like this today, I’d probably look hardest at The Cyper System or WoD games. Umbran’s suggestion of Alternity would probably be good too- I haven’t seen the new version, but I hear good things.
I suppose what works best for YOU and YOURS depends largely on:
1) what system feels comfortable
2) what flavor of sci-fantasy fusion you’d want to run. A mash-up between things your group finds cool will start a positive feedback loop.
Those factors will do a lot towards getting player buy-in.
Best campaign I ever ran was a supers game set in the Space:1889 setting using HERO, with all kinds of things thrown in. Player buy-in was total. That campaign lasted years.
But when I tried essentially the same thing a 2 decades later using Mutants & Masterminds 2nd as the system engine, it was a complete flop. It crashed & burned in months, for a variety of reasons (including my own screw-ups).
Just because I think an Adam Strange/Flash Gordon type setting with some low-magic fantasy or sci-fant elements- “Jedis”, psionics, TK/PK, Clairvoyants, Illusionists, Shapechangers, Healers, etc., would cool doesn’t mean anyone else will.
