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The American Heart Association guidelines for prevention of infective endocarditis (IE) in 2007 reduced the groups of congenital heart disease (CHD) patients for whom antibiotic prophylaxis was indicated. The evidence base in CHD patients is limited. We sought to determine the risk of IE in children with CHD.We performed a population-based analysis to determine the cumulative incidence and predictors of IE in children (0–18 years) with CHD by the use of the Quebec CHD Database from 1988 to 2010. In 47 518 children with CHD followed for 458 109 patient-years, 185 cases of IE were observed. Cumulative incidence of IE was estimated in the subset of 34 279 children with CHD followed since birth, in whom the risk of IE up to 18 years of age was 6.1/1000 children (95% confidence interval, 5.0–7.5). In a nested case-control analysis, the following CHD lesions were at highest risk of IE in comparison with atrial septal defects (adjusted rate ratio, 95% confidence interval): cyanotic CHD (6.44, 3.95–10.50), endocardial cushion defects (5.47, 2.89–10.36), and left-sided lesions (1.88, 1.01–3.49). Cardiac surgery within 6 months (5.34, 2.49–11.43) and an age of <3 years (3.53, 2.51–4.96; reference, ages 6–18) also conferred an elevated risk of IE.In a large population-based cohort of children with CHD, we documented the cumulative incidence of IE and associated factors. These findings help identify groups of patients who are at the highest risk of developing IE.