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Introduction: Postoperative HAI cause important morbidity and mortality in children undergoing cardiac surgery for congenital heart disease. Multiple risk factors for HAI have been identified. Perioperative antibiotic prophylaxis (PAP) regimens can decrease surgical site infections (SSI) but are extrapolated from data in adults. Hypothesis: Compliance with PAP reduces the risk of SSI in children undergoing cardiac surgery. Most causative organisms will be resistant to PAP. Methods: We performed an IRB-approved retrospective cohort study to assess HAI in children?18 yo who had cardiac surgery from July 2010-Dec 2011. Potential pre-, intra-, and post-operative risk factors and adherence to PAP were abstracted from the electronic medical record. Risk factors were assessed. Results: Of the 430 patients who underwent cardiac surgery, 24 developed 27 HAI within 3 mo of surgery. These were: 4 central-line associated bloodstream infections (CLABSI), 4 non-CLABSI bacteremias, 4 endocarditis, 5 SSI, and 7 ventilator-associated pneumonias. Appropriate PAP was provided to 54% vs. 70% of patients with and without an HAI (HR 1.97, CI95% 0.88, 4.40, p=0.097), but no significant difference in SSI was observed. Sixty percent of SSI pathogens were non-susceptible to PAP. In univariate analysis, prior hospitalization; length of surgery, cardiopulmonary bypass, and cross-clamp time; PICU and hospital length of stay (LOS); delayed sternal closure; duration of medical devices; and blood transfusions, as well as use of PAP >48 hrs, were potential risk factors. Intra-operative transfusions (HR 2.61, CI95% 0.91, 7.46, p=0.07), post-operative transfusions (HR 4.29, CI95 1.24, 14.79, p=0.02), and PICU LOS (HR 1.02, CI95% 1.01, 1.04, p<0.0001) remained associated with HAI in multivariate analysis by Cox proportional hazards. Conclusions: Adherence to PAP can decrease risk of HAI in children undergoing cardiac surgery. Blood transfusions and PICU LOS are significant risk factors for HAI, likely reflective of severity of illness. Further studies should assess potential interventions to reduce HAI, including the role of the age of transfused blood products, improving adherence to PAP, and skin decontamination.