The present study was designed to determine whether stress hormones and subjective responses to a psychological stressor were different in nonalcoholic offspring from families with a history of alcohol dependence (family history positive, FHP) than in nonalcoholic offspring without a family history of alcohol dependence (family history negative, FHN). Forty-five healthy subjects (17 FHP, 28 FHN), between the ages of 18 and 29 years, completed the Trier Social Stress Test (TSST). The TSST consisted of 5 min of public speaking followed by 5 min of mental arithmetic. Three baseline and five post-TSST blood samples were drawn. Pre-and post-TSST self-report measures of anxiety were obtained. Cortisol, adrenocorticotropin (ACTH), and prolactin significantly increased in response to the TSST in the entire study sample (F (1,187) ÂŒ 70.22, po0.001, F (1,143) ÂŒ 33, po0.001, and F (1,134) ÂŒ 14.37, po0.001, respectively). Cortisol responses were influenced by an interaction between racial composition and family history of alcoholism (F (1,57) ÂŒ 4.50, p ÂŒ 0.038). Among Caucasian subjects, FHP subjects had greater cortisol response to the TSST compared to FHN subjects (F (1,57) ÂŒ 4.45, p ÂŒ 0.039). No family history effect was identified in African-American subjects. Adrenocorticotropin responses did not differ between FHP and FHN subjects. Adrenocorticotropin response was positively associated with baseline ACTH levels in FHN subjects (t ÂŒ 5.02, p ÂŒ o0.001), but not in FHP subjects. Prolactin responses did not differ between FHP and FHN subjects. Anxiety response scores (post-TSST scores minus pre-TSST scores) were higher in FHP subjects compared with FHN subjects (z ÂŒ Ă2.67, p ÂŒ 0.007). In addition, anxiety response scores were positively associated with cortisol response levels to the TSST in FHN subjects (t ÂŒ 4.52, po0.001). In contrast, anxiety responses were negatively associated with cortisol responses in FHP subjects (t ÂŒ Ă2.30, p ÂŒ 0.024). Our findings are consistent with theories that greater reactivity to stress is associated with greater risks for alcoholism. Furthermore, the findings suggest that the association between the hypothalamic-pituitary-adrenal axis hormonal response and the subjective perception of stress might be deranged in offspring of alcoholics.