Prostate stem cell antigen (PSCA), a 123-amino acid cell surface glycoprotein, is highly expressed in both local and metastatic prostate cancers as well as in a large proportion of bladder and pancreatic cancers. PSCA overexpression correlates with a high risk of recurrence after primary therapy for prostate cancer. We have reported previously that anti-PSCA monoclonal antibody (mAb) 1G8 inhibits tumor growth, prevents metastasis, and prolongs the survival of mice inoculated with human prostate cancer cell lines and xenografts. The current study was undertaken to elucidate the mechanism of action of anti-PSCA antibody therapy. In particular, we asked whether antitumor activity resulted from recruitment of an immune response or a direct effect on the tumor cell itself. In vitro assays show that both intact 1G8 and F(ab')2 fragments of 1G8 induce prostate cancer cell death. The anti-PSCA antibody-induced cell death is caspase independent and requires antigen cross-linking. These results were confirmed in in vivo models in which both 1G8 and F(ab')2 fragments were able to inhibit prostate tumor formation and growth equally. These results suggest that the anti-PSCA mAb 1G8 acts by a direct, Fc-independent mechanism to inhibit prostate tumor growth both in vitro and in vivo.