SummaryObjective-Differences in the hypothalamic-pituitary-adrenal (HPA) axis response to stress may confer differences in susceptibility to a variety of diseases. We hypothesized that whites would differ from blacks in HPA axis response to a psychological stressor.Design-Healthy subjects aged 18-30 were recruited from Baltimore, Maryland. At initial assessment, they completed psychometric tests measuring anxiety, mood, and personality. Subjects then participated in the Trier Social Stress Test (TSST), which consisted of 10 min of public speaking and mental arithmetic exercises. Subjective anxiety was measured immediately pre-and post-TSST. Race effects on cortisol, adrenocorticotrophin (ACTH), and prolactin responses to the TSST were analyzed by GEE longitudinal analysis methods. The analysis controlled for gender, baseline hormone levels, socioeconomic factors, anxiety, mood, and dimensions of personality.Results-Ninety-eight subjects participated in the TSST. Whites had 36% greater relative mean cortisol response than blacks (95% CI: 10%-67%, P = 0.004). Whites had significantly higher mean ACTH compared to blacks at 25 min after the start of the TSST, (35%, 95% CI: 16%-58% greater, P < 0.001). There was no difference in prolactin response. Of note, whites and blacks did not differ in subjective anxiety response to the TSST.Conclusions-In sum, we found that whites have a more robust HPA axis response to the TSST compared with blacks, even after controlling for several socioeconomic and psychological factors. In contrast, we observed no difference in prolactin response. There were no differences in subjective response to the TSST to explain the difference in HPA axis response. Further study is indicated to explain this finding and to test whether it can be extrapolated to other forms of stress.