Endotoxin, a lipopolysaccharide (LPS), is a bacterial cell wall product instrumental in producing deleterious host responses to infection. This LPS appears to act, in part, by triggering release of endogenous mediators such as cytokines. Repeated exposures to endotoxin produce attenuated responses to this molecule. To examine the mechanisms and biologic consequences of this tolerance to LPS, Wistar rats were subjected to a 14-day course of LPS administration. Tolerance to LPS with regard to anorexia, weight loss, and acute-phase responses was noted. Attenuation of these physiologic responses was accompanied by abrogation of circulating cytokine appearance in response to endotoxin, suggesting that tolerance to LPS is in part due to a decreased production of cytokines. Tolerance to LPS also diminished the response to a subsequent infected thermal injury, as measured by food intake, body weight, fibrinogen levels, and mortality. Thus, clinical conditions involving repeated exposure to LPS may modify the host's responses to subsequent injury. The attenuated responses to injury accompanying the decreased production of cytokines further implicate cytokines in the pathogenesis of injury and disease.