Objective Prokinetic medications are used in premature infants to promote motility and decrease time to full enteral feeding. Erythromycin and metoclopramide are the most commonly used prokinetic medications in the neonatal intensive care unit (NICU), but their safety profile is not well defined. Methods We conducted a large retrospective cohort study using data from 348 NICUs managed by the Pediatrix Medical Group. All infants exposed to ≥1 dose of erythromycin, metoclopramide, or both, from a cohort of 887,910 infants discharged between 1997 and 2012 were included. We collected laboratory and clinical information while infants were exposed to erythromycin or metoclopramide and described the frequency of laboratory abnormalities and clinical adverse events. Results Metoclopramide use increased from 1997–2005 and decreased from 2005–2012, while erythromycin use remained stable. Erythromycin use was most often associated with a diagnosis of feeding problem (40%), while metoclopramide was most often associated with a diagnosis of gastroesophageal reflux (59%). The most common laboratory adverse event during exposure to erythromycin or metoclopramide was hyperkalemia (8.6/1000 infant days on erythromycin and 11.0/1000 infant days on metoclopramide). Incidence of pyloric stenosis was greater with erythromycin than with metoclopramide (10/1095, 0.9% vs. 76/19,001, 0.4%, p=0.01), but odds were not significantly increased after adjusting for covariates (odds ratio=0.52 [95% CI: 0.26, 1.02], p=0.06). More infants experienced an adverse event while treated with metoclopramide than with erythromycin (odds ratio=1.21 [95% CI: 1.03, 1.43]). Conclusion Metoclopramide was associated with increased risk of adverse events compared to erythromycin. Studies are needed to confirm safety and effectiveness of both drugs in infants.