Postmenopausal women receiving estrogen-replacement therapy (ERT) regulate body temperature (T_b) at a lower level than women not receiving hormone replacement therapy (untreated) and women using estrogen plus progesterone therapy (E + P), but it is not clear if reproductive hormones alter T_b by directly acting on central thermoregulatory centers or indirectly via a secondary mediator(s). The purpose of the present investigation was to examine the possible involvement of pyrogenic cytokines and cyclooxygenase (COX) products (e.g., prostaglandins) in the regulation of T_b in three groups of postmenopausal women (8 ERT, 7 E + P, and 8 untreated). We measured ex vivo secretion of cytokine agonists [tumor necrosis factor (TNF)- and interleukin (IL)-1 and -6] and modifiers (IL-2 soluble receptor, IL-1 receptor antagonist, soluble TNF receptor type I, soluble TNF receptor type II, soluble IL-6 receptor, and soluble glycoprotein 130) from peripheral blood mononuclear cells and thermoregulatory responses at rest and during 1 h of passive whole body heating in the postmenopausal women before and after 3 days of placebo or aspirin (50 mg · day¹ · kg¹). With and without aspirin, the ERT group had a lower baseline rectal temperature (T_re; 0.44°C, P < 0.004) and a reduced T_b threshold for cutaneous vasodilation (0.29°C and 0.38°C, P < 0.01) compared with the untreated and E + P groups, respectively. In the placebo condition, waking morning oral temperature (T_or) correlated with ex vivo secretion of the proteins associated with IL-6 bioactivity. Aspirin caused significant reductions in waking T_or in the E + P group and in baseline T_re in the untreated group. However, the difference in thermoregulation brought about by steroid hormone treatment could not be explained by these relatively modest apparent influences by cytokines and COX products. Therefore, the altered thermoregulation induced by reproductive steroid therapy appears to occur via a mechanism distinct from a classic infection-induced fever.