Endotoxin (LPS) characteristically provokes both fever and the acute-phase reaction (APR). The present studies were undertaken to determine whether these two responses are mutually dependent or controlled separately. Rabbits were injected with LPS (2 μg/kg, IV) or exposed to heat (37±1° C) such that the patterns and magnitudes of the body temperature (Tco) rises (1.6±0.5° C) were similar. While the plasma levels of Fe and Zn decreased, and those of Cu and N-acetylneuraminic acid (NANA) increased significantly after LPS-induced fever, no such changes occurred after heat-induced hyperthermia. In a subsequent study, different rabbits were exposed to cold (3±1° C), first furred, then sheared. While furred, they thermoregulated by cutaneous vasoconstriction, whereas, while shaved, they additionally increased their metabolic rates. However, in neither case were the plasma levels of Fe, Zn, Cu, or NANA different in comparison to their pre-cooling values (Ta=22±1° C). It would seem, therefore, that the acute-phase blood responses to LPS (and ultimately, to endogenous pyrogen [EP]) probably are not mediated merely by the rise in the Tco or by the concomitantly induced vascular and/or thermogenic effectors of fever; but rather, the APR appears to be a regulated, separate response to LPS/EP. © 1984 Springer-Verlag.