Fas/APO-1 is a cell surface protein known to trigger apoptosis in a variety of cell types upon specific antibody binding. Although extensively studied on normal and malignant hematopoietic cells, little is known about Fas/APO-1 on nonhematopoietic cells. In the study presented here, we have examined Fas/APO-1 expression and function on 11 human tumors of nonhematopoietic origin. By flow cytometric analysis, Fas/APO-1 was expressed on 10 of the 11 tumors at levels comparable to those previously reported for lymphoid cells sensitive to the cytolytic effects of anti-Fas. Despite abundant cell surface expression, only 4 of the 10 Fas-positive tumors were sensitive to the cell-killing effects of anti-Fas. Moreover, anti-Fas enhanced the growth of 2 of 10 Fas-positive tumors. Additional studies using cycloheximide demonstrated that de novo protein synthesis was required for anti-Fas-triggered growth stimulation and, at least in one case, was responsible for the resistance to antibody-induced apoptosis. The biological effects initiated by anti-Fas engagement, however, were not correlated with endogenous bcl-2 expression. This report documents that: (a) Fas/APO-1 is widely expressed on cultured nonhematopoietic tumors; (b) the inherent susceptibility to anti-Fas-induced apoptosis is not correlated with expression of the Fas/APO-1 protein; (c) Fas/APO-1 engagement can result in growth enhancement; and (d) protective/growth-promoting proteins other than bcl-2 may contribute to the diverse spectrum of biological effects induced by anti-Fas engagement of the Fas/APO-1 protein.