In addition to well documented vascular growth promoting effects, ANG II exerts proapoptotic effects that are poorly understood. IGF-1 is a potent survival factor for human vascular smooth muscle cells (hVSMC), and its antiapoptotic effects are mediated via the IGF-1 receptor (IGF-1R), through a signaling pathway involving phosphatidylinositol 3-kinase and Akt. We hypothesized that there would be crosstalk between ANG II proapoptotic effects and IGF-1 survival effects in hVSMC. To investigate ANG II-induced apoptosis and the potential involvement of IGF-I, we exposed quiescent and non-quiescent hVSMC to ANG II. ANG II induced apoptosis only in non-quiescent cells but stimulated hypertrophy in quiescent cells. ANG II induced apoptosis was characterized by marked inhibition of Akt phosphorylation and stimulation of membrane FasL expression and caspase 8 activation, and a reduction in soluble FasL expression. Adenovirally mediated overexpression of Akt rescued hVSMC from ANG II induced apoptosis. IGF-1R activation increased Akt phosphorylation and soluble FasL expression and these effects were completely blocked by co-incubating hVSMC with ANG II. In conclusion, ANG II induced apoptosis of hVSMC is characterized by marked inhibition of Akt phosphorylation and stimulation of an extrinsic cell death signaling pathway via upregulation of membrane FasL expression, caspase 8 activation, and a reduction in soluble FasL expression. Furthermore, ANG II antagonizes the antiapoptotic effect of IGF-1 by blocking its ability to increase Akt phosphorylation and soluble FasL. These findings provide novel insights into ANG II-induced apoptotic signaling and have significant implication for understanding ANG II-induced remodeling in hypertension and atherosclerosis.