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Background Congenital heart disease (CHD) is the most common risk factor for infective endocarditis (IE) in children. Staphylococcus aureus is among the most common organisms to cause IE, yet there are little data describing the risk factors for invasive S aureus disease in children with CHD. We examined the epidemiology of S aureus infections in children with CHD. Methods Patients with a history of CHD and S aureus infection were identified from a surveillance study of S aureus infections at Texas Children's Hospital. Clinical and laboratory data from medical records were reviewed. All isolates were screened for the presence of the antiseptic tolerance gene qacA/B. Dichotomous variables were compared with Fisher's exact test and continuous variables with Mann-Whitney U tests, and two-tailed P values of <.05 were considered significant. Results Two hundred forty-eight S aureus infections developed in 216 patients with CHD. Methicillin resistance was seen in 53.6% of isolates. Surgical site infections accounted for 28.2% of cases and bacteremia accounted for 20.4% of cases. Bacteremia was associated with IE in 29.5% of the episodes. Infective endocarditis was more often associated with prolonged bacteremia, thrombocytopenia, and a higher C-reactive protein (CRP) compared with uncomplicated bacteremia. The qacA/B gene was found in 16.9% of isolates and was associated with bacteremia and prolonged hospitalization. Conclusions Staphylococcus aureus is an important cause of morbidity among children with CHD. Infective endocarditis was common with S aureus bacteremia in this population; in addition, prolonged bacteremia, thrombocytopenia, and CRP >10 mg/dL may serve as diagnostic adjuncts for IE. qacA/B-positive isolates are associated with adverse clinical outcomes. [ABSTRACT FROM PUBLISHER]