Angiotensin II (Ang II) has been implicated in the regulation of smooth muscle cell proliferation after vascular injury, but the molecular mechanisms of this effect remain obscure. The aims of the present study were 1) to determine if Ang II was mitogenic (in a defined serum-free medium) for aortic smooth muscle cells derived from spontaneously hypertensive rats, either alone or in combination with epidermal growth factor, basic fibroblast growth factor, or platelet-derived growth factor-BB; and 2) to determine if the Ang II effects were mediated by autocrine production of transforming growth factor-β (TGF-β). Results demonstrated that Ang II increased the proliferative response of smooth muscle cells to epidermal growth factor or platelet-derived growth factor-BB. Ang II alone and in combination with basic fibroblast growth factor induced a small delayed increase (48–72 hours after treatment) in DNA synthesis and [3H] thy mi-dine labeling indexes without an increase in cell number. Ang II effects were at least partially mediated by autocrine production of active TGF-β in that 1) treatment with Ang II increased TGF-β activity in conditioned media and 2) TGF-β neutralizing antibody inhibited Ang II-induced increases in DNA synthesis. However, treatment with exogenous TGF-β at concentrations induced by Ang II failed to elicit a mitogenic response, thus implicating other autocrine factors in mediation of Ang II effects. Results suggest a potential mechanism whereby Ang II might regulate smooth muscle cell mitogenesis after vascular injury.