Background Unintentional injury is a leading cause of infant mortality. Purpose To examine the role of caregiver health literacy in infant injury prevention behaviors. Methods A cross-sectional analysis of data collected in 2010-2012 from a randomized trial at four pediatric clinics was performed in 2012-2013. Caregiver health literacy was assessed with the Short Test of Functional Health Literacy in Adults. Caregiver-reported adherence to American Academy of Pediatrics-recommended injury prevention behaviors was assessed across seven domains: (1) car seat position; (2) car seat use; (3) sleeping safety; (4) fire safety; (5) hot water safety; (6) fall prevention; and (7) firearm safety. Results Data were analyzed from 844 English- and Spanish-speaking caregivers of 2-month-old children. Many caregivers were non-adherent with injury prevention guidelines, regardless of health literacy. Notably, 42.6% inappropriately placed their children in the prone position to sleep, and 88.6% did not have their hot water heater set <120°F. Eleven percent of caregivers were categorized as having low health literacy. Low caregiver health literacy, compared to adequate health literacy, was significantly associated with increased odds of caregiver non-adherence with recommended behaviors for car seat position (AOR=3.4, 95% CI=1.6, 7.1) and fire safety (AOR=2.0, 95% CI=1.02, 4.1) recommendations. Caregivers with low health literacy were less likely to be non-adherent to fall prevention recommendations (AOR=0.5, 95% CI=0.2, 0.9). Conclusions Non-adherence to injury prevention guidelines was common. Low caregiver health literacy was significantly associated with some injury prevention behaviors. Future interventions should consider the role of health literacy in promoting injury prevention. © 2014 American Journal of Preventive Medicine.