In this study we have verified the mitogenic effect of urokinase-type (u-PA) and tissue-type plasminogen activators (t-PA) on human normal fibroblasts. We report that both PAs can induce DNA replication and cell division in serum-deprived cultured human skin fibroblasts. The activity of u-PA and t-PA is, respectively, three- and twofold more potent than that exerted by epidermal growth factor (EGF) with an activity slightly lower (50-60%) than that induced by basic fibroblast growth factor (bFGF). The u-PA and t-PA, but not plasmin, induced DNA synthesis, which could be neutralized by anti-u-PA and anti-t-PA antibodies, respectively, but was insensitive to aprotinin treatment. The addition of anti-u-PA-receptor (u-PAR) monoclonal antibodies to the assays selectively suppressed the mitogenic effect exerted by u-PA, but not that of t-PA, and the amino-terminal fragment of u-PA, containing the EGF-like domain and the kringle module, did not elicit any mitogenic activity. Anti-bFGF antibodies completely suppressed the mitogenic activity of bFGF, but did not have any effect on that of u-PA and t-PA; the activity of both PAs was inhibited by anti-fibronectin IgG concentrations ineffective on bFGF. These results indicate that PAs may be considered growth factors of human fibroblasts.