Cardiovascular fitness and physical activity have been positively associated with executive cognitive functioning (i.e., planning, scheduling, coordinating, response inhibition, and working memory), which rely on the frontal region of the brain. Recent studies suggest that the benefit is particularly strong in middle-aged individuals who carry the Apolipoprotein (ApoE) e4 allele, a known genetic risk factor for Alzheimer's disease (AD). However, there have been no studies to determine this interactive relationship in adolescents. Therefore, the present study examined if cardiovascular fitness mediates the relationship between genotype and cerebral cortical responses in college-age males during a frontally-mediated executive challenge. Twenty nine e4 carriers (N=29; 15 high-fit, 14 low-fit) and thirty non-carriers (N=30; 15 high-fit, 15 low-fit) were stratified by cardiovascular fitness. Cognitive function was assessed by neuroelectric response, event-related potentials (ERPs) recorded at 11 sites (F3, Fz, F4, C3, Cz, C4, P3, Pz, P4, O1 and O2) to both an auditory Go-nogo executive task (ECF) and a non-executive Oddball task (non-ECF). The P300 amplitude, which is indicative of the recruitment of attentional resources, exhibited by the high-fit e4 carriers was higher relative to that observed in the low-fit e4 carriers during both the ECF and non-ECF tasks. Importantly, the high-fit e4 carriers were also undifferentiated from both groups of the non-carriers. Furthermore, high-fit individuals, regardless of genotype, exhibited shorter P300 latency than did the low-fit individuals at sites Fz, Cz and Pz during ECF task and site Pz during non-ECF task. The current findings revealed genetic specificity in the relationship between cardiovascular fitness and the brain processes indexed by P300 amplitude function during late adolescence in response to both ECF and non-ECF challenge, with greater benefit incurred for the ECF task. The results suggest that cardiovascular fitness in e4 carriers is protective against the susceptibility to the liabilities (i.e., hypometabolism and cortical thinning) associated with this allele.