This study assessed the ability of executive cognitive functioning (ECF) to predict reactive aggression in boys at high and low risk for substance abuse using a 2-year prospective design. ECF is defined as the self-regulation of goal-directed behavior. Reactive aggression involves impulsive hostile reactions committed with little forethought. ECF was measured using five neuropsychological tests in 198 10- to 12-year-old boys with (SA+) and without (SA-) a paternal history of substance abuse/dependence. Reactive aggression was measured, 2 years later, using a composite index of items derived from two self-report measures. It was hypothesized that ECF would predict reactive aggression, and that this relation would be stronger for the SA+ compared with the SA- boys. SA+ subjects demonstrated lower ECF scores and higher reactive aggression scores, compared with SA- controls. ECF predicted reactive aggression in the SA+ group (beta = 0.37, p = 0.001), but not in the SA- group (beta = 0.09, p = NS). This suggests that compromised ECF may be a risk factor for reactive aggression in SA+ youth. The hypothesis that the relation between ECF and reactive aggression is a manifestation of a mild dysfunction of the prefrontal cortex is discussed.