Define a role for Fas-FasL in oxygen-induced retinopathy and explore the mechanism of pigment-epithelium-derived growth factor (PEDF) inhibition in this model. Seven-day-old mice C57BL/6J (B6), FasL-defective (B6-gld), or Fas-defective (B6-lpr) mice were exposed to 75% oxygen for 5 days (postnatal day [P]7-P12) and returned to room air. On day P17, vascular architecture was assessed microscopically after perfusion with FITC-dextran, and preretinal nuclei were quantified by PAS and hematoxylin staining. In some experiments, mice were treated intraperitoneally with PEDF. Vascular architecture and preretinal nuclei counts were compared with those in PBS-treated control animals. Oxygen-induced retinopathy was significantly increased in FasL-defective gld mice compared with wild-type B6 animals. This was manifested by an increase in the number of microaneurysms, neovascular tufts, and preretinal nuclei. PEDF treatment prevented retinopathy in B6, B6-gld, and B6-lpr mice. Fas-FasL interactions regulate the extent of oxygen-induced retinal neovascularization. The inhibition of neovascularization in B6 gld, and B6-lpr mice by PEDF suggests that Fas-FasL interactions are probably not the mechanism for inhibition in this model.