It has been hypothesized that transforming growth factor beta (TGF-beta) may prevent immune-mediated glioma cell elimination; however, previous work has also indicated that increased TGF-beta may lead to reduced proliferation, induction of apoptosis, and enhancement of Fas-induced apoptosis. We have investigated the role of TGF-beta in the progression of malignant glioma using an immunocompetent murine model. SMA 560 malignant glioma cells were stably transfected with constructs that resulted in over- or underproduction of active TGF-beta1. Using these cell lines, we have shown that (a) TGF-beta1 inhibits induction of antitumor cytotoxicity when the tumor cells are given s.c. but not when they are given intracranially; (b) Fas/APO-1 is expressed on SMA 560 cells in vitro and in vivo, SMA 560 cells are susceptible to TGF-beta1- and Fas-induced apoptosis in vitro, and TGF-beta1 and Fas act synergistically to induce glioma cell death; (c) increased levels of endogenous TGF-beta1 production by SMA 560 cells lead to increased sensitivity to Fas-mediated apoptosis; (d) overproduction of endogenous TGF-beta1 reduces the rate of s.c. SMA 560 tumor growth and also reduces the tumorigenicity of tumors located in the central nervous system, with opposite effects observed with underproduction of TGF-beta1 using antisense cell lines; and (e) the observed changes in growth parameters in vivo were associated with increased rates of apoptosis in TGF-beta1-overproducing cells. Taken together, these results indicate that, despite decreased induction of CTL responses, the dominant net effect of TGF-beta1 on the growth of the SMA 560 murine high-grade glioma in vivo is growth inhibition. This contrasts with results seen with non-central nervous system malignant tumors in immunocompetent animals, in which TGF-beta1 production provides a major growth advantage.