Angiotensin II (ANG II) has long been known for its pressor and growth-promoting effects, which are both mediated by the AT₁ receptor. By contrast, the AT₂ receptor has recently been reported to mediate inhibition of proliferation through as yet undefined mechanisms. We report here that in bovine adrenal fasciculata cells ANG II by itself does not affect growth but inhibits basic fibroblast growth factor (bFGF)-induced DNA synthesis and blocks the cells in G₁ phase. Consistent with this, ANG II inhibits cyclin D₁ expression and cyclin D₁-associated kinase activity. The antimitogenic effect of ANG II is partly mimicked by the AT₂-selective agonist CGP-42112. It is also blocked partly and in an additive fashion by the AT₁- and AT₂-selective antagonists losartan and PD-123319, indicating the contribution of both receptor subtypes to this response. AT₁-dependent antiproliferation is selectively blocked by the cyclooxygenase inhibitor indomethacin and restored by prostaglandin E₂, whereas AT₂-receptor-mediated inhibition of growth is suppressed by the tyrosine phosphatase inhibitors orthovanadate and bpV(pic). Both pathways are, however, pertussis toxin sensitive. We hypothesize that, in fasciculata cells, the AT₁ receptor inhibits bFGF-induced proliferation by stimulating prostaglandin synthesis, whereas the AT₂ receptor mediates its effect through a pathway that requires protein tyrosine phosphatase activation.