Objective: Peripheral blood mononuclear cell (PBMC) dysfunction occurs following major abdominal surgery and correlates with an increased rate of septic complications. Studies have shown that dehydroepiandrosterone (DHEA) restores cell-mediated immune responses after trauma-hemorrhage in mice. Nonetheless, it remains unknown whether DHEA has any salutary effects on depressed PBMC function in surgical patients. Design: Laboratory experiment. Setting: University laboratory. Patients: Fifteen patients undergoing major abdominal surgery. Interventions: Blood samples were obtained preoperatively and 2 hrs postoperatively. Measurements and Main Results: PBMCs were cultured with 33% plasma in the presence or absence of DHEA (10-10 M, 10 -8 M physiologic concentration, 10-6 M, 10-5 M). In an additional set of samples, the estrogen receptor antagonist tamoxifen (10-6 M) was added. The release of proinflammatory cytokines (interleukin-1β, interleukin-6, and tumor necrosis factor-α) was measured in the supernatants by enzyme-linked immunosorbent assay. Abdominal surgery resulted in depressed interleukin-1β and tumor necrosis factor-α release by PBMC. Addition of DHEA to the culture medium, however, significantly improved the release of interleukin-1β and tumor necrosis factor-α and stimulated the interleukin-6 release capacity of PBMC. This effect was most pronounced for a concentration of 10-5M DHEA. The immunomodulatory effect of DHEA on PBMC cytokine release was completely blocked by tamoxifen. In contrast, the modulatory effect of DHEA was enhanced by the addition of postoperative plasma. Conclusions: DHEA stimulates proinflammatory cytokine release capacities of human PBMCs following major abdominal surgery. The estrogen receptor appears to be involved in mediating the immunomodulatory effect of DHEA. Thus, DHEA might be a useful adjunct for preventing immunosuppression in surgical patients. Copyright © 2005 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.