Transforming growth factor β-1 (TGF-β1) is a potent inhibitor of hepatocyte growth both in vivo and in vitro. In this study, we analyzed the effects of TGF-β1 on both naturally occurring and diethylnitrosamine- induced hepatocarcinogenesis using single transgenic TGF-β1 and double transgenic c-myc/TGF-β1 mice in which the expression of both transgenes was targeted to the liver. Hepatocellular tumors developed spontaneously in 59% (10 of 17) of the TGF-β1 mice by 16-18 months of age. Coexpression of TGF- β1 and c-myc transgenes in the liver accelerated hepatic tumor growth in both the presence and absence of carcinogenic treatment. Moreover, diethylnitrosamine-initiated tumors in the c-myc/TGF-β1 mice showed a high rate of malignant conversion associated with a reduced expression or lack of TGF-β receptor type II. The results suggest that overexpression of TGF-β1 may contribute to liver carcinogenesis and that loss of TGF-β receptor type II transduced inhibitory growth signals and up-regulation of c-myc are critical steps in liver tumor progression.