The thermal effect of fever, an evolutionarily conserved acute-phase response, has been associated with better survival and a shorter duration of disease in cases of infection. The molecular consequence of this beneficial fever response is poorly understood. To determine the influence of hyperthermia on human monocytes, which are important for the recognition and elimination of pathogens, twelve healthy volunteers were immersed in a 39.5 degrees C hot water bath to increase their body temperature. The expression of the endotoxin receptor CD14 and the complement receptor CD11b increased after the hot water bath (P < 0.05), whereas the expression of the selectin CD62L, which mediates the initial attachment of leukocytes at the endothelium during inflammation, was downregulated after hyperthermia (P < 0.05). Comparable changes in monocyte receptor expression were observed after in vitro hyperthermia. Furthermore, 3 hours after in vivo hyperthermia, the response of monocytes to endotoxin was enhanced in an ex vivo lipopolysaccharide stimulation assay, as expressed by a greater TNF-alpha release (P < 0.05). We conclude that the thermal effect of fever directly activates monocytes, which increases their ability to respond to bacterial challenge.