The purpose of these studies was to determine whether systemic administration of IFN-alpha can inhibit the expression of basic fibroblast growth factor (bFGF) in human transitional cell carcinoma, reduce its angiogenesis, and thus inhibit its growth in the bladder wall of nude mice. In vitro incubation of the highly metastatic 253J B-V cells and the IFN-alpha-resistant 253J B-V IFNR cells with noncytostatic concentrations of IFN-alpha down-regulated the steady-state mRNA transcripts and protein production of bFGF. IFN-alpha-insensitive and IFN-alpha-resistant cells were implanted in the bladder wall of nude mice. Systemic administration of IFN-alpha decreased the in vivo expression of bFGF, decreased blood vessel density in the tumors, and inhibited tumor growth of both IFN-alpha-insensitive and IFN-alpha-resistant cells. These data suggest that in addition to its well-documented antiproliferative effects, IFN-alpha can inhibit the growth of human bladder cancer cells by inhibition of angiogenesis.