Background: Surgical site infections (SSIs) following open heart surgery involving cardiopulmonary bypass (CPB) among pediatric patients are healthcare-associated infections associated with significant morbidity and mortality. At a pediatric acute-care facility, an increase in SSI incidence prompted an epidemiologic review. We describe the incidence of cardiac SSIs at our hospital; we identified risk factors and areas of practice variation to inform improvement initiatives. Methods: SSI cases following CPB at our hospital have been identified through routine surveillance using NHSN definitions since January 2016. An increase in cases was noted in mid-2018, prompting a common cause analysis with stakeholders across the preoperative, intraoperative, and postoperative care continuum. Areas of practice variability were identified, and an epidemiologic review was performed to determine risk factors among cases compared to noncases between January 2016 and August 2018. The rate of SSIs and 95% confidence intervals were estimated, and univariate logistic regressions were fitted to estimate unadjusted odds ratios (ORs) for the association between each of the predetermined preoperative, intraoperative, and postoperative factors and developing an SSI. Results: Overall, 139 patients underwent surgery involving CPB between January 1, 2016, and August 31, 2018. Preoperative bathing was infrequently documented (9% among cases vs 5% among noncases; P = .56). Operating room observations identified frequent door openings and equipment crowding. Moreover, 11 patients (7.9%) developed a cardiac SSI, with 6 (14.3%) occurring in the first 8 months of 2018 (P = .067). There were no predominant pathogens; 3 of 11 cases were associated with methicillin-susceptible Staphylococcus aureus. Also, 9 cases were classified as deep incisional or organ-space SSI. Each hour increase in total CPB duration was associated with a 63% increase in odds of developing an SSI (OR, 1.626; 95% CI, 1.041–2.539). Each additional day of intubation (OR, 2.400; 95% CI, 1.203–4.788) and peritoneal dialysis (OR, 1.767; 95% CI, 1.070–2.919) during the first 3 days postoperatively were also associated with increased SSI risk. Postoperative documentation of wound assessment occurred in 60% of patients, with no difference between cases and noncases (55% vs 67%; P = .42). Conclusions: Using a mixed-methods approach, preoperative bathing, increased operating room traffic, and postoperative care around wounds and invasive devices were identified as areas of improvement toward safer surgical care. Although no unique organism or process explained the increased rate, determining risk factors and areas of practice variability through stakeholder engagement provided insight into opportunities to prevent SSIs.