Retinopathy of prematurity is a disease commonly affecting extremely premature babies. Indomethacin is widely used in the perinatal period. The goal of the present study was to test the hypothesis that indomethacin will improve retinopathy in a mouse model when administered during the period of injury (hyperoxia exposure) to the developing retinal vasculature. C57BL6 mice pups were exposed to 75% oxygen from postnatal d 7 through 12. Indomethacin was administered along with the oxygen exposure as a single subcutaneous dose of 0.5 mg/kg/d for 5 d. Animals were killed on postnatal d 17 through 20. The severity of retinopathy was assessed by a retinopathy scoring system of fluorescein-conjugated dextran-perfused retinal flat mounts and by quantitation of extraretinal nuclei by use of periodic acid-Schiff-stained retinal sections. Animals that received indomethacin during hyperoxia exposure had a significantly lower median (25th, 75th quartile) retinopathy score 5 (4.5, 6) compared with animals that received oxygen [8 (7.5, 10)]. Animals given indomethacin during hyperoxia exposure had a significantly lower extraretinal nuclei count per section (13.3 +/- 4.6) (mean +/- SD) compared with animals that were oxygen exposed (41.9 +/- 14.7). Indomethacin did not affect the normal development of the retinal vasculature or the growth of the animals. The data show that indomethacin improves oxygen-induced retinopathy when administered concurrently with the injury phase without affecting the normal retinal development or growth of the animals.