I don't know about the most, but I've been watching The Bob Newhart Show and I've seen Teri Garr, Henry Winkler, Howard Hessman and Sharon Gless (Cagney & Lacey) as guest stars. And that just in half of one season.

When watching The Mary Tyler Moore Show on DVD, I recall seeing Henry Winkler and Penny Marshall among some of the guest stars.

It's something that would happen with any long running show.

The Larry Sanders Show had:

Jeffrey Tambor
Jeremy Piven
Sarah Silverman
Jon Stewart (before the Daily Show)
Megan Mullaly appeared in an episode