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A single treatment of low‐temperature, long‐duration, whole‐body hyperthermia of either severe combined immunodeficient (SCID) mice bearing human breast tumor xenografts or Balb/c mice bearing syngeneic tumors for 6–8 hr can cause a temporary reduction of tumor volume and/or a growth delay. In both animal model systems, this inhibition is correlated with the appearance of large numbers of apoptotic tumor cells. Because this type of mild heat exposure, comparable to a common fever, is not itself directly cytotoxic, other explanations for the observed tumor cell death were considered. Our data support the hypothesis that this hyperthermia protocol stimulates some component(s) of the immune response, which results in increased antitumor activity. In support of this hypothesis, increased numbers of lymphocyte‐like cells, macrophages, and granulocytes are observed in the tumor vasculature and in the …