Background Inhibitors of gastric acid (IGA) are used for upper gastrointestinal bleeding or gastroesophageal reflux in preterm infants. The resultant increase in gastric pH may enhance the growth of pathogens and increase the risk of necrotizing enterocolitis (NEC). Our systematic review examined the association between IGA and NEC in preterm infants. Methods Standard methodology of systematic reviews was followed. PubMed, Embase, Cochrane, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were searched in August 2012. Results One case-control and one prospective cohort study (n = 11,346), both evaluating H2-blockers as IGA, were included. Meta-analysis showed a significant association between NEC and IGA (odds ratio [OR]: 1.78, 95% confidence interval [CI]: 1.4, 2.27, p <0.00001). The prospective cohort study found higher incidence of infection (sepsis, pneumonia, urinary tract infection) with IGA (37.4% versus 9.8%, OR: 5.5, 95% CI: 2.9 to 10.4, p <0.001). Conclusions Exposure to H2 receptor antagonists may be associated with increased risk of NEC and infections in preterm infants. © 2013 by Thieme Medical Publishers, Inc.