Background Lower cerebral blood flow (CBF) has previously been documented preoperatively in neonates with congenital heart disease (CHD). However, it remains unclear if these CBF deficits persist over the life span of CHD survivors following heart surgery. When exploring this question, it is critical to consider the sex differences in CBF that emerge during adolescence. Therefore, this study aimed to compare global and regional CBF between postpubertal youth with CHD and healthy peers and examine if such alterations are related to sex. Methods and Results Youth aged 16 to 24 years who underwent open heart surgery for complex CHD during infancy and age- and sex-matched controls completed brain magnetic resonance imaging, including T1-weighted and pseudo-continuous arterial spin labeling acquisitions. Global gray matter CBF and regional CBF in 9 bilateral gray matter regions were quantified for each participant. Compared with female controls (N=27), female participants with CHD (N=25) presented with lower global and regional CBF. In contrast, there were no differences in CBF between male controls (N=18) and males with CHD (N=17). Concurrently, female controls had higher global and regional CBF compared with male controls, with no differences in CBF between female and male participants with CHD. CBF was lower in individuals with a Fontan circulation. Conclusions This study provides evidence of altered CBF in postpubertal female participants with CHD despite undergoing surgical intervention during infancy. Alterations to CBF could have implications for later cognitive decline, neurodegeneration, and cerebrovascular disease in women with CHD.