In this study, the cold pressor test (CPT) was used to test a model of the effects of acute pain on 10 HIV+ and 10 HIV- adults. Participants were exposed to the CPT for a maximum of 5 minutes. Blood samples were collected immediately before, immediately after, and 1 hour after the CPT. Variables included immune measures (CD4+, CD8+, and CD16+56+ lymphocyte number, CD4+CD8+ lymphocyte ratio and NK cell cytotoxicity), cardiovascular reactivity (heart rate, systolic and diastolic blood pressure), anxiety, perceived pain intensity and perceived self-efficacy. Effects of pain were generally consistent across HIV+ and HIV- groups, with no between-group differences across time in immune responses, state anxiety and diastolic blood pressure. Within-subjects differences across time averaged over both groups were significant for NK cell cytotoxicity, CD8+ and CD16+56+ lymphocyte numbers, anxiety and heart rate. Significant nonlinear trends were observed for CD16+56+ lymphocyte numbers, NK cell cytotoxicity and state anxiety in both groups and for heart rate in the HIV+ group only. Perceived pain intensity was significantly associated with state anxiety (r = .65), systolic (r = −.56) and diastolic (−.52) blood pressure and CD4+ lymphocyte number (r = .48). Heart rate and trait anxiety were significantly associated with all immune variables. Associations were positive for CD4+ lymphocyte number and inverse for all other immune measures. Associations between perceived self-efficacy and both perceived pain intensity and anxiety were inverse, as predicted, but not significant. Overall, the direction and strength of observed relationships provided some support for the theoretical model on which the study was based. Generally, responses to acute pain were consistent and did not differ by HIV status.