OBJECTIVE: This study tested the hypothesis that preterm infants who had a blood gas derangement on at least 2 of the first 3 postnatal days are at increased risk for more severe retinopathy of prematurity (ROP). METHOD: 1,042 infants born before 28 weeks' gestational age (GA) were included. An infant was considered to be exposed if his/her blood gas measure was in the highest or lowest quartile for GA on at least 2 of the first 3 postnatal days. RESULTS: Multivariable models adjusting for confounders indicate that exposure to a PCO(2) in the highest quartile predicts ROP (stage 3, 4 or 5: OR = 1.6, 95% CI = 1.1-2.3); zone 1: 2.0, 1.1-3.6; prethreshold/threshold: 1.9, 1.2-3.0; plus disease: 1.8, 1.1-2.9). Estimates are similar for a low pH for zone 1 (2.1, 1.2-3.8), prethreshold/threshold (1.8, 1.1-2.8), but did not quite achieve statistical significance for ROP stage 3, 4, or 5 (1.4, 0.9-2.0) and plus disease (1.5, 0.9-2.4). A PaO(2) in the highest quartile for GA on at least 2 of the first 3 postnatal days was associated with a doubling of the risk of ROP in zone 1 (2.5, 1.4-4.4) and of prethreshold/threshold disease (2.1, 1.4-3.3), a 70% risk increase for plus disease (1.7, 1.04-2.8), while a 40% risk increase for ROP stage 3 or higher did not achieve statistical significance (1.4, 0.96-2.0). CONCLUSION: Infants exposed to high PCO(2), low pH and high PaO(2) appear to be at increased risk of more severe ROP.