Despite developments in preventative and medical therapy, infective endocarditis (IE) carries a high rate of mortality. Risk factors for mortality are unknown in pediatric and adult patients with congenital heart disease (CHD). We determined the risk factors for in-hospital mortality in pediatric and adult patients with CHD. A retrospective observational cohort study was conducted from January 1997 to December 2001 in Japan. Of the 239 patients for whom complete data were available, 216 patients with CHD were identified. Outcomes were alive or deceased. The proposed modified Duke’s criteria identified 137 patients, aged 1 month to 62 years with a median of 12 years, with IE. In-hospital mortality was 10%. Four risk factors were independently associated with mortality by stepwise logistic regression analysis: (1) vegetation size ≥20 mm (odds ratio 40.6, 95% confidence interval 2.42 to 681); (2) age <1 year (odds ratio 19.5, 95% confidence interval 1.74 to 219); (3) presence of heart failure (odds ratio 7.16, 95% confidence ratio 1.34 to 38.4); and (4) Staphylococcus aureus as a causative organism (odds ratio 5.68, 95% confidence interval 1.16 to 27.9). Surgical intervention emerged as a predictive factor for lower in-hospital mortality (odds ratio 0.045, 95% confidence interval 0.003 to 0.70) by stepwise logistic regression analysis. In conclusion, surgical intervention, which decreases the risk of in-hospital mortality, should always be considered.