OBJECTIVE Most cases of necrotizing enterocolitis (NEC) are sporadic, but outbreaks in hospital settings suggest an infectious cause. Our neonatal intensive care unit (NICU) experienced an outbreak of methicillin-sensitive Staphylococcus aureus (MSSA). We aimed to assess whether the enhancement of infection prevention and control measures would be associated with a reduction in the number of cases of NEC. DESIGN Retrospective chart review. SETTING A 24-bed, university-affiliated, inborn level 3 NICU. PARTICIPANTS Infants of less than 30 weeks gestation or birth weight ≤ 1,500 g admitted to the NICU between January 2007 and December 2008 were considered at risk of NEC. All cases of NEC were reviewed. INTERVENTIONS Infection prevention and control measures, including hand hygiene education, were enhanced during the outbreak. Avoidance of overcapacity in the NICU was reinforced, environmental services (ES) measures were enhanced, and ES hours were increased. RESULTS Two hundred eighty-two at-risk infants were admitted during the study. Their gestational age and birth weight (mean ± SD) were 28.2 ± 2.7 weeks and 1,031 ± 290 g, respectively. The proportion of NEC was 18/110 (16.4%) before the outbreak, 1/54 (1.8%) during the outbreak, and 4/118 (3.4%) after the outbreak. After adjustment for gestational age, birth weight, gender, and singleton versus multiple births, the proportion was lower in the postoutbreak period than in the preoutbreak period (P < .002). CONCLUSION Although this observational study cannot establish a causal relationship, there was a significant decrease in the incidence of NEC following implementation of enhanced infection prevention and control measures to manage an MSSA outbreak.