My own feeling on it is (ignoring the genre mix part of the question) is that at some point you need to deal with the places where the systems actively rub up against each other. What I mean by this usually is there are mechanics where values are designed to interact with other values, not just themselves. These are often, but not always combat situations.
To use a couple examples I'm familiar with:
I want to let Player One use a Fantasy Hero character and fight a Runequest monster. The former is going to have a combat value that needs to be compared to another combat value, and a set of damage values that assume certain numbers that are present in the target; the latter doesn't directly interact with the defender in attacking, but its assumed that the target will have a defensive skill (a Parry or Dodge depending on the particulars of that version of RQ) that is rolled against the attack; its damage doesn't also likely map up against the passive defenses of the target properly.
In addition, as mentioned by someone upthread, the two system's initiative/combat time management are vastly different, and at least the Hero System character may be partly dependent on some of the structure of that to work right.
I can see it being much more possible to butt up characters from different characters in the D&D and D&D adjacent spheres.