Administration of staphylococcal enterotoxin B (SEB) to BALB/c mice was found to induce a cytokine release syndrome hallmarked by weight loss and hypoglycemia. A neutralizing monoclonal antibody against gamma interferon (IFN-gamma) given before SEB counteracted weight loss and prevented hypoglycemia. This protective effect of anti-IFN-gamma antibody was associated with decreased IFN-gamma levels in serum; tumor necrosis factor (TNF) and interleukin-6 (IL-6) levels remained unchanged. A monoclonal anti-IL-6 antibody, known for its ability to cause accumulation of biologically active IL-6 in the circulation, did not modify SEB-induced body weight loss or hypoglycemia. Levels of TNF, IFN-gamma, and IL-6 in serum were all more elevated in anti-IL-6-treated mice than in corresponding SEB-challenged control mice. In D-galactosamine-sensitized mice, SEB-induced weight loss but not hypoglycemia was more severe, resulting mostly in death within 24 h. Higher levels of biologically active TNF and IFN-gamma in serum were noted in these mice than in mice receiving SEB only. In D-galactosamine-sensitized mice, anti-IFN-gamma antibody did prevent hypoglycemia but failed to reduce the severity of the syndrome. Again, TNF levels in anti-IFN-gamma-treated mice remained unchanged. Pretreatment with anti-IL-6 antibody temporarily attenuated SEB-induced hypoglycemia in sensitized mice. Thus, at 6 h post-SEB injection, anti-IL-6-treated mice were less hypoglycemic than corresponding controls. However, at 24 h, hypoglycemia was significantly aggravated. Concomitantly, IL-6 levels were dramatically increased. Neither anti-IFN-gamma nor anti-IL-6 antibody treatment modulated mortality levels in D-galactosamine-sensitized mice. The data obtained with anti-IFN-gamma antibody clearly indicate that endogenous IFN-gamma is instrumental in bringing about hypoglycemia and body weight loss in mice exposed to SEB but also that hypoglycemia is not a crucial determinant of mortality in D-galactosamine-sensitized mice. The data obtained with anti-IL-6 antibody indicate that endogenous IL-6 is involved in regulating the levels of TNF and IFN-gamma in serum.