Background: Interactions among known risk factors for retinopathy of prematurity (ROP) remain to be clarified. Objectives: The aim of this study was to identify risk factors associated with ROP and to explore the interrelationships between prominent risk factors for ROP. Methods: From an institutional cohort of 1,646 very preterm newborns with gestational age <30 weeks or birth weight <1,501 g, we selected infants with a gestational age <30 weeks who met the criteria for ROP screening (n = 622) for a nested case-control analysis. Results: Of the 622 eligible newborns, 293 (47%) were diagnosed with ROP. From multivariable analyses, gestational age <26 weeks (OR 2.9, CI 1.7–4.9), oxygen exposure at 28 days (OR 1.7, CI 1.0–2.7), and neonatal sepsis (OR 2.1, CI 1.4–3.2) emerged as prominent risk factors for ROP. Oxygen- associated ROP risk was more prominent among infants of 23–25 weeks’ gestational age, while infection-associated ROP risk was higher among infants born at 28–29 weeks. The OR for the joint effect of all 3 risk factors (23.5) was higher than would have been expected under the additive (8.6) and the multiplicative (16.5) patterns of interaction. Conclusions: Our study suggests that neonatal sepsis, oxygen exposure, and low gestational age are not only independently associated with a significantly increased risk of ROP, but also interact beyond additive and even multiplicative patterns.