The mechanism by which simple hemorrhage profoundly impairs the proliferative response of T lymphocytes to mitogen and alloantigen, produces a defect in interleukin-2 generation, and increases the susceptibility to sepsis remains unknown. Since antigen presentation (AP) by the macrophage (Mφ) plays a critical role in the antigen-specific activation of T-helper cells and lymphokine production, we investigated whether the function of the Mφ as an AP cell is altered following hemorrhage. C3H/HEJ mice were bled to a mean BP of 35 mm Hg, maintained at that level for 1 hr, and then resuscitated. There was no mortality with this model. Control mice were not bled but otherwise treated identically. Immediately after resuscitation the mice were sacrificed and peritoneal Mφ (PMφ) as well as splenic adherent cells (SAC) were harvested. AP function was tested by coculturing different numbers of PMφ and SAC with D10.G4.1 cells (2 × 104 cells/well) in the presence of conalbumin (300 μg/ml). This T-helper cell clone proliferates upon recognition of conalbumin in the context of Iak (a Mφ surface membrane glycoprotein), thus directly reflecting Mφ AP capability. After 72 hr of incubation, the cultures were pulsed with [3H]thymidine and harvested. D10.G4.1 proliferations induced via AP by PMφ and SAC from hemorrhaged-resuscitated mice were 29 and 24% of control, respectively (P < 0.05). Thus, we conclude that AP by Mφ following hemorrhage is defective despite adequate resuscitation, a mechanism which could explain the state of immunosuppression and enhanced susceptibility to sepsis. © 1989.