Background: The effect of activation of endogenous transforming growth factor-β (TGF-β) on smooth muscle cell apoptosis was assessed in human saphenous vein. Methods: Segments of human saphenous vein, obtained at the time of bypass graft surgery, were cultured for 14 days. During this time, smooth muscle cells accumulated in the intima as a result of proliferation and migration, partly counterbalanced by apoptotic cell death. Results: Addition of exogenous TGF-β<sub>1</sub> had no effect on smooth muscle cell proliferation or apoptosis. However, antibody neutralization of endogenous TGF-β<sub>1</sub> caused significant increases in smooth muscle cell death in the media and intima without any change in proliferation. A plasmin inhibitor (α-N-acetyl- L-lysine methyl ester), a specific urokinase-type plasminogen activator (uPA) inhibitor (amiloride) and an anti-catalytic anti-uPA antibody all caused decreases in the tissue content of active TGF-β and increases in smooth muscle cell death in the media and intima. Conclusions: These data suggest that the amount of TGF-β in human saphenous vein is sufficient, when in the active form, to protect smooth muscle cells against apoptosis. Adding exogenous TGF-β<sub>1</sub> has no beneficial effect, but decreasing the amount of active TGF-β causes smooth muscle cells to undergo apoptosis. Plasmin, generated by uPA, appears to be an important activator of endogenous latent TGF-β.