Although it is known that interferon-γ synthesis and macrophage functions are depressed after hemorrhage, it remains to be determined whether systemic administration of interferon-γ has any effect on hemorrhage-induced depression of macrophage and splenocyte functions. To study this, C3H/HEN mice were bled to a mean blood pressure of 35 mm Hg, maintained for 60 minutes, and followed by adequate fluid resuscitation. The mice then received either 1000 units interferon-γ or saline solution (vehicle). Peritoneal (pMφ) and splenic (sMφ) macrophages and splenocytes were isolated 24 hours later. PMφ antigen presentation was measured by coculturing pMφ with the D10.G4.1 cell clone. Major histocompatibility complex class II (Ia) antigen expression was determined by direct immunofluorescence. Cytokine release by pMφ, sMφ, and splenocytes was assessed with specific bioassays. For survival studies, mice were subjected to sepsis 3 days after hemorrhage. Treatment with interferon-γ restored (p ≤ 0.05) hemorrhage-induced suppression of pMφ antigen presentation capacity and Ia antigen expression and increased (p ≤ 0.05) interleukin-1 and tumor necrosis factor release by pMφ and sMφ, as well as splenocyte proliferation (p ≤ 0.05). Interferon-γ also decreased (p ≤ 0.007) the susceptibility to sepsis after hemorrhage. Thus interferon-γ represents a potent agent for treating hemorrhagic shock- induced immunosuppression and for increasing the ability of the host defense system to combat bacterial infections after hemorrhage.