While substance use disorder (SUD) in parents significantly increases the risk for adolescent substance abuse, the biological foundation of SUD is not clearly understood. Available data showed that neurobehavioral disinhibition in the offspring may mediate the association between SUD in parents and adolescent substance use and SUD in young adulthood. Neurobehavioral disinhibition refers to a deficiency in modulating cognition, affect, and behavior appropriate to environmental circumstances. Adolescents who take psychoactive drugs and young adults who qualify for SUD have been found in many studies to exhibit characteristics reflecting neurobehavioral disinhibition. This study was undertaken to determine whether HPA axis activity was related with parental SUD and neurobehavioral disinhibition in offspring. Another goal was to determine if there were sex differences in the relationships between family history of SUD, HPA axis activity, and neurobehavioral disinhibition. The sample consisted of 202 10- to 12-year-old biological offspring who met DSM-III-R criteria for lifetime SUD and 258 youth whose fathers had no lifetime SUD. Disinhibition was assessed across three psychological dimensions: affect, behavior, and cognition. HPA axis activity was measured by saliva cortisol level. The results showed that children of SUD fathers (HAR) were more likely to demonstrate features of affect, behavior, and cognitive disinhibition compared to children of normal fathers (LAR). The HAR group had lower cortisol levels, but none of the comparisons attained statistical significance. Review of the data by sex showed that boys and girls were different in both predisposition to, and correlates of, disinhibition. Boys were more likely than girls to score high on disinhibition. Cortisol level was negatively correlated with severity of neurobehavioral disinhibition. That is, the disinhibition was higher and cortisol level lower in boys compared to girls. As a consequence of these findings, it is tentatively concluded that boys and girls differ with respect to biochemical indicators of stress reactivity underlying neurobehavioral disinhibition, a phenotype connected with the liability for SUD. Tables, references