Retinopathy of prematurity (ROP) is a common disease of premature infants. It is characterized by an abnormal proliferation of blood vessels in the developing retina and is the leading cause of childhood blindness in developed countries. This article describes a systematic approach to prospectively reduce the incidence of ROP in a newborn intensive care unit (NICU). We realized the need for improvement when we reviewed comparative data indicating that our rates of ROP were higher than those in NICUs in our local area, across the United States, and around the world. After informal efforts appeared successful in significantly reducing ROP, we designed and implemented a more structured approach to ROP prevention that included improvements in practice related to oxygen administration and monitoring. An evidence-based guideline was developed, and education was provided to all direct care providers. We also standardized bedside oxygen delivery equipment and implemented new parameters related to nasal cannula weaning. Rates of ROP, severe ROP, and ROP requiring surgical intervention were reduced by more than 50% during the first year and more than 75% by the end of the second year after implementation of our unit-based program.