From the perspective of language design, Hissp strives to be more directly homoiconic, representing s-expressions as Python tuples. Hy is more of an abstract sexpr-to-Python compiler, with s-expressions represented as custom data types, rather than Python primitives.

From the perspective of usability, Hissp is very minimalistic overall. Whereas Hy is both much more Python-like in its user experience and provides much more of a batteries-included experience like you'd find in Common Lisp or Clojure (and in fact its standard library takes a lot of inspiration from both).

I consider Hissp as more of an interesting experiment in language design than a practical programming language. Whereas I think Hy is very practical and I've been very happy to use it for various scripts over the years.

That's not to say Hissp is a bad project by any means. It's impressive, and I admire its dedication to its own principled consistency. I just don't find it very practical.

The downside of Hy is that they've gone through several radical design changes over the years, but that finally seems to be stabilizing.