We have shown that a soluble receptor for vascular endothelial growth factor (sVEGFR), which adsorbs VEGF and may function as a dominant-negative receptor, suppresses tumor angiogenesis and enhances apoptosis of cancer cells, thereby inhibiting tumor growth [Cancer Res 60 (2000) 2169-2177]. In the present study, using as many as 11 cancer cell lines, we tested two hypotheses: (a) that a soluble fibroblast growth factor receptor-1 (sFGFR1) might inhibit tumor angiogenesis and growth in sVEGFR-resistant cancers, and (b) that combining sFGFR1 with sVEGFR might produce an enhanced inhibitory effect. In two cell lines derived from human lung cancer, H460 and A549, both of which produce a considerable amount of FGF-2, sVEGFR and a soluble receptor for angiopoietin-1 were both ineffective; however, sFGFR1 inhibited tumor angiogenesis and growth, demonstrating the critical role that FGFs play in some cancers. In three cell lines (QG56 from lung cancer, T3M4 and Panc1 from pancreatic cancer), which produced both VEGF and FGF-2 at detectable levels, combined sVEGFR and sFGFR1 produced an enhanced inhibitory effect compared to their individual effects. The combined usage of sVEGFR plus sFGFR1 suppressed tumor growth in all cancer cell lines tested, suggesting possible effectiveness of this strategy against a wide range of cancers.