Recent cloning of the cDNA for Fas/Apo-1 and its ligand has revealed that they belong to the tumor necrosis factor (TNF) receptor and TNF family, respectively, and play an important role in apoptosis (programmed cell death). Like TNF, antibodies against the Fas antigen (anti-Fas) have been shown to be cytotoxic to Fas-expressing cells. Whether Fas, like TNF receptor, also mediates proliferation of normal human diploid fibroblasts (HDF), is not known. In this study, we show that HDF expresses Fas antigen and the engagement of this antigen signals proliferation of these cells in a dose-dependent manner. Unlike TNF receptor, however, Fas-mediated proliferation of HDF could not be blocked by orthovanadate, a tyrosine phosphatase inhibitor. The difference in the signaling was further evident from our observation that TNF induced the expression of interleukin-6 but anti-Fas did not. Overall, our results demonstrate for the first time that besides cell killing, Fas also mediates proliferation of HDF and that its mechanism is different from that of TNF receptor.