IL-2 to synergistically enhance IFN- γ production (3, 14) and the central role of IFN- γ in IL-12–mediated tumor responses (1, 3, 15) suggested that IFN- γ could also be an important component of IL-12/pulse IL-2–induced antitumor responses. In patients with metastatic melanoma or renal cell carcinoma, an initial increase, followed by a decrement in circulating IFN- γ levels, may be observed in some patients treated with repeated doses of IL-12 alone, while sustained induction of IFN- γ production and elevation of circulating IFN- γ levels correlated with clinical responsiveness (16). Thus, an enhanced ability of IL-12/pulse IL-2 to induce IFN- γ might keep levels of this cytokine above a critical threshold for tumor response. These findings are par-The induce complete regression of metastatic murine renal carcinoma. Here, we show that overt tumor regression induced by IL-12/pulse IL-2 is preceded by recruitment of CD8 + T cells, vascular injury, disrupted tumor neovascularization, and apoptosis of both endothelial and tumor cells. The IL-12/IL-2 combination synergistically enhances cell surface FasL expression on CD8 + T lymphocytes in vitro and induces Fas and FasL expression within tumors via an IFN- γ –dependent mechanism in vivo. This therapy also inhibits tumor neovascularization and induces tumor regression by mechanisms that depend critically on endogenous IFN- γ production and an intact Fas/FasL pathway. The ability of IL-12/pulse IL-2 to induce rapid destruction of tumor-associated endothelial cells and regression of established metastatic tumors is ablated in mice with a dysregulated Fas/FasL pathway. The com-mon, critical role for endogenous IFN- γ and the Fas/FasL pathway in early antiangiogenic effects and in antitumor responses suggests that early, cytokine-driven innate immune mechanisms and CD8 + T cell–mediated responses are interdependent. Definition of critical early molecular events engaged by IL-12/IL-2 may provide new perspective into optimal therapeutic engagement of a pro-ductive host-antitumor immune response.