Fever is induced by both exogenous products like endotoxin, and endogenous cytokines, most notably IL-1 and IL-6, and tumour necrosis factor (TNF). These mediators are believed to interact with the hypothalamus, to induce enhanced body temperature. However, little is known about the biological effects of fever on the function of the immune system. We here report that a 90-min pulse of mild hyperthermia (40 degrees C) induces enhanced proliferation of peripheral blood mononuclear cells (PBMC). This proliferative response was completely inhibited by antibodies to MHC class II, which had no effect on mitogen-induced proliferation of PBMC. The enzyme-linked immunospot (ELISPOT) assay is a sensitive method for detection of single cells secreting antibodies or cytokines. A 90-min pulse of mild hyperthermia (40 degrees C) induced a significantly enhanced immunoglobulin production in PBMC, as determined by ELISPOT, indicating B cell activation. The T cell cytokine pattern both with and without stimulation with hyperthermia differed between individuals. Enhanced interferon-gamma (IFN-gamma) secretion was noted at 39-41 degrees C. This IFN-gamma response was inhibited by antibodies to MHC class II and thus was MHC class II-restricted and dependent on antigen-presenting cells. None of the individuals tested showed IL-4 response after stimulation with hyperthermia. These findings favour the notion that fever may play an important role in immune responses, and it is possible that fever may act as a physiological adjuvant, with effects on the immune system both in infection and inflammation of other origins.