Sex has been linked to differential outcomes for cardiovascular disease in adults. We examined potential sex differences in outcomes after pediatric cardiac surgery. We retrospectively analyzed data from the Pediatric Cardiac Care Consortium (1982-2007) by using logistic regression to evaluate the effects of sex on 30-day within-hospital mortality after pediatric (<18 years old) cardiac operations and its interaction with age, risk category, z-score for weight, and surgical year for the whole cohort. Of 76 312 operations, 55% were in boys. Unadjusted mortality was similar for boys and girls (5.2% versus 5.0%, P=0.313), but boys were more likely to have cardiac surgery as a neonate and to have more complex operations. After adjustment, the overall test of any association between postsurgical mortality and sex was significant (P=0.002), but the overall test of any interaction was not (P=0.503). However, a potential age-dependent sex effect on postsurgical mortality was observed among infants subjected to high-risk operations, with girls doing worse during the first 6 months of life. Patient sex has a significant effect on mortality after pediatric cardiac operations, with an increased risk of death in early infancy for girls after high-risk cardiac operations. This age-dependent relationship supports a sex-related biological effect on postoperative cardiovascular stress.