Caveolin-1, the major caveolar protein, directly interacts with IGF-I Receptor (IGF-IR) and its intracellular substrates. To determine the role of caveolin-1 in IGF-IR signaling, we transfected H9C2 cells with small interfering RNA specific for caveolin-1 (Cav-1-siRNA). The selective down regulation of caveolin-1 (90%) was associated with a smaller reduction of caveolin-2 while caveolin-3 expression was unaffected. A significant reduction of IGF-IR tyrosine phosphorylation in Cav-1-siRNA H9C2 cells was found compared to H9C2 control cells (Ctr-siRNA). The reduced IGF-IR auto phosphorylation resulted in a decrease of IRS-1, Shc and Akt activation. In addition, in Cav-1-siRNA H9C2 cells IGF-I did not prevented apoptosis, suggesting that caveolin-1 is required to mediate the anti-apoptotic effect of IGF-I in cardio myoblasts. The down regulation of caveolin-1 decreased IGF-IR activation and affected the ability of IGF-I to prevent apoptosis after serum withdrawal also in human umbilical vein endothelial cells (HUVECs). These results demonstrate that: 1) caveolin-1 down regulation negatively affects IGF-IR tyrosine phosphorylation; 2) this effect causes a reduced activation of IRS-1, Shc, Akt; 3) caveolin-1 is involved in IGF-IR antiapoptotic signaling following serum deprivation.