We examined HPA axis response to 50 mg oral naltrexone compared with placebo in 17 healthy male and female nonalcoholic subjects, approximately half of whom had a positive family history of alcoholism (FH+) and half of whom who did not (FH-). Mood response and naltrexone biotransformation were also examined at various intervals. Subjects participated in two morning test sessions (50 mg naltrexone or identical placebo pill) after an overnight stay in the Rockefeller University GCRC. For the total sample, ACTH and cortisol significantly increased after naltrexone compared with placebo (p <.05). Secondary analyses showed the FH+ subgroup had a different pattern of response over time compared with the FH- subgroup, with heightened ACTH and cortisol, and decreased vigor ratings, during naltrexone (p <.05). The results demonstrate that orally administered naltrexone acutely disinhibits the HPA axis, and that individuals with an assumed greater biological vulnerability to addiction, by virtue of familial alcoholism, had altered regulation of the HPA axis in part under the control of the endogenous opioid system. 166 words.