Abstract Hypoxia is the main stimulus for neovascularization in the retina. Insulin-like growth factor-I (IGF-I) is thought to be one of the mediators of this process. Severe persistent hypoxia, as occurs in central retinal artery occlusion, is associated with less retinal neovascularization than relative hypoxia. To study the influence of different types of hypoxia on the IGF system, we used a model of neonatal rat retina that responds with neovascularization to a relative hypoxic stimulus produced by alternating oxygen concentrations in the respired air. We studied the influence of 24-hour hypoxia (10% oxygen), 48-hour hyperoxia (75% oxygen), and relative hypoxia (shifting from 48 hours in 75% oxygen to 24 hours in room air) on the gene expression of IGF-I, IGF-I receptor (IGF-IR), and IGF binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 in retina using a solution hybridization RNase protection assay. Hypoxia induced a significant increase in retinal IGF-IR (178%), IGFBP-2 (227%), and IGFBP-3 (317%) mRNA; however, retinal IGF-I mRNA was reduced, as well as serum growth hormone (GH). Relative hypoxia caused a similar but less pronounced trend in the gene expression of IGF-IR and the binding proteins, whereas retinal IGF-I mRNA was unchanged and serum GH was elevated. Both hypoxia and relative hypoxia may cause IGF system stimulation in the retina through upregulation of IGF-IR and IGFBPs. This stimulation may result in neovascularization. However, during hypoxia, low levels of tissue oxygenation and reduced local production of IGF-I may impede the neovascularization process.