To determine whether hemorrhage without major tissue trauma can itself produce immunosuppression, the effect of hemorrhage on the lymphocyte response to T-cell mitogen in endotoxin-resistant C3H/HEJ mice was measured. The mice were bled to achieve a mean blood pressure of 35 mm Hg, maintained at that level for one hour, and then adequately resuscitated. On days 1 through 10 thereafter, the proliferative responses of the splenocytes to concanavalin A were measured and allogeneic mixed lymphocyte reaction was performed. The proliferative responses to mitogen stimulation as well as the results of mixed lymphocyte reaction studies indicated that marked immunosuppression occurred at day 1. Immunosuppression persisted for at least five days following hemorrhage, as evidenced by mitogen stimulation assay. Another group of mice was subjected to sepsis three days after hemorrhage and resuscitation. The mortalities in the sham-hemorrhage and hemorrhage groups following sepsis were 58% and 100%, respectively. Thus, a significant depression of cellular immunity occurred following simple hemorrhage despite adequate resuscitation, and this immunosuppression enhanced the susceptibility to sepsis. © 1987, American Medical Association. All rights reserved.