Febrile responses to bacterial pathogens are attenuated near term of pregnancy in several mammalian species. It is unknown however whether this reflects a fundamental physiological adaptation of female rats, or whether it is specific to pregnancy. The aims of this study therefore were; (1) to determine whether febrile responses to the bacterial endotoxin lipopolysaccharide (LPS) are attenuated in female versus male rats, and if so, to identify possible mechanisms involved in modulating this, and (2) to assess whether plasma concentrations of the anti-inflammatory cytokine, interleukin-1 receptor antagonist (IL-1ra), an important regulator of fever, are dependent on the physiological state of the female and could therefore be involved in modulating febrile responses. We found febrile responses were attenuated in cycling female versus male rats, and also in near term pregnant dams versus cycling females, following intraperitoneal (ip) injection of LPS (0.05 mg kg^-1). Plasma levels of IL-1ra were significantly greater in female rats after injection of LPS, particularly during pregnancy, versus males. This was accompanied by attenuated levels of hypothalamic IL-1 and COX-2 mRNA, two key mediators of the febrile response, in female rats. Furthermore, increasing plasma levels of IL-1ra in male rats by administration (ip) of the recombinant antagonist attenuated hypothalamic mRNA levels of these mediators following LPS. These data suggest there is a fundamental difference in febrile response to LPS between the genders that is likely regulated by IL-1ra. This may be an important mechanism that protects the developing fetus from potentially deleterious consequences of maternal fever during pregnancy.