Hypercarbia has been suggested as a risk factor for retinopathy of prematurity. We investigated the effect of raised inspired carbon dioxide on oxygen-induced retinopathy in the neonatal rat. Newborn rats raised in expanded litters (n = 25 each) were exposed to cycles of hyperoxia (80% O 2) and hypoxia (10% O 2) for 7 days, followed by room air recovery for 5 days. During cyclic oxygen exposure, 3 litters (n = 75) were exposed to 10% CO 2 (PaCO 2 78 mm Hg ± 6; mean ± SD) and 3 litters (n = 75) were exposed to 0.2% CO 2 (PaCO 2 45 mm Hg ± 7). Animals were sacrificed on day 13 and retinae were analyzed using fluorescein perfusion and ADPase staining techniques. Neovascularization occurred in 85% of rats exposed to high CO 2 compared to 52% of rats exposed to low CO 2 (p = 0.001). The severity of neovascularization, in clock hours, was also greater in the rats exposed to high CO 2 (p < 0.001). Exposure to high CO 2 results in an increased incidence and severity of neovascularization in a rat model for oxygen-induced retinopathy. Our results support the suggestion that hypercarbia may be a risk factor for retinopathy of prematurity.