Although the naloxone challenge has been used to draw inferences about the dynamics of the stress response, this procedure has never actually been compared "head to head" with a psychological stressor. In the present study, we asked 14 healthy volunteers to complete the naloxone challenge and the Trier Social Stress Test in an outpatient GCRC laboratory setting so that the degree of correspondence between the two procedures could be examined. Findings indicated that subjects who had greater ACTH responses to naloxone also had greater ACTH responses to the psychologically-induced stressor. This was true for both ACTH peak (r=0.57; p<0.04) and ACTH AUC response (r=0.64; p<0.02) measures; none of the cortisol summary score measures correlated significantly across the two challenges. Associations were also found between subjects' baseline personality characteristics and their ACTH responses to each of the challenges. Furthermore, the kinds of characteristics that predicted greater ACTH response to the pharmacological challenge were similar to the kinds of characteristics that predicted ACTH response to the psychological challenge. In general, higher scores on the NEO dimensions of Extraversion and Openness predicted greater ACTH responses. These findings give preliminary evidence that novelty-seeking behavior may be associated with HPA axis lability. The commonalities in personality predictors between the two challenges further support the notion that a common biological substrate may be, at least partially, responsible for the similarities in responses. However, caution should be used in assuming that responses to naloxone directly parallel responses to physiological stress.