Choroidal neovascularization (CNV) is a debilitating complication of age-related macular degeneration and a leading cause of vision loss. Along with other angiogenic factors like vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-1 and its receptor, IGF-1R, have been implicated in CNV. IGF-1 is produced in neurons and retinal pigment epithelium (RPE) but its targets and impact in CNV are not understood. IGF-1 immunoreactivity was abundant throughout surgically isolated human CNV tissues and RPE cells were immunopositive for IGF-1R. Cultured RPE cells obtained from CNV tissues expressed IGF-1R. IGF-1 stimulation of cultured cells from CNV tissues induced monophasic sustained rises in intracellular free Ca(2+). VEGF concentration in the medium of unstimulated RPE cell cultures from CNV tissues increased with time to a steady-state (8h) which was increased twofold by IGF-1 stimulation. Thus, in RPE cells IGF-1 stimulates the second messenger Ca(2+) and increases VEGF secretion which, in turn, induces neovascularization.