Although tumor necrosis factor (TNF) has been implicated in sepsis-induced mortality, its role in the pathophysiology of hemorrhagic shock (HS) remains ill defined. We studied three groups of acutely anesthetized mice undergoing HS to determine the role of TNF in HS mortality. Shock was initiated in each group after heparinization by arterial bleeding of 4 mL/100 g body weight followed by 12 mL/100 g body weight resuscitation with normal saline at 1 hour. The C3H/HeJ mice (n = 14), characterized by a genetic defect in macrophage production of TNF and other cytokines in response to endotoxin, were compared with the closely related C3H/HeN strain (n = 18), which do produce TNF. A second group of C3H/HeN mice were passively immunized to TNF by pretreatment with 2.5 mg/kg anti-murine TNF antibody (Ab) before HS. In contrast to the high TNF levels measured following HS in C3H/HeN controls, post-HS TNF was undetectable in C3H/HeJ mice. Five-day survival rate and survival time were significantly greater in C3H/HeJ mice when compared with C3H/HeN controls. Anti-TNF Ab pretreatment of C3H/HeN mice abolished the increase in TNF but did not improve survival. The data demonstrate a striking improvement in survival of TNF-deficient C3H/HeJ mice following severe HS. However, the improved survival does not appear to result from deficient TNF production, since Ab pretreatment did not decrease HS mortality. The improved survival in C3H/HeJ mice suggests that cytokines other than TNF may play a role in the pathophysiology of HS.