Summary:The lymphokine interleukin‐2 (IL‐2) has been shown to enhance natural cell‐mediated cytotoxicity, the generation of cytolytic T lymphocytes, and several other aspects of cellular immune function. The gene coding for human IL‐2 has been cloned, and recombinant IL‐2 will be available for clinical trials in patients with neoplastic, infectious, and immunodeficiency diseases. The present investigation was undertaken to determine if IL‐2 was similar to interleukin‐1 (IL‐1) in its ability to induce fever and the acute‐phase response. These studies were based on recent work with recombinant human interferon (IFN)‐&agr;, which is intrinsically pyrogenic and capable of producing fever by inducing the synthesis of prostaglandin E2(PGE2). The prospect that IL‐2 might exert similar physiologic effects is of critical concern since elevated temperature, PGE2, and acute‐phase reactants may profoundly inhibit natural cell‐mediated cytotoxicity. Our studies have shown that recombinant human IL‐2 is not intrinsically pyrogenic in rabbits at doses as high as 10,000 units/kg when administered by a single intravenous injection. In contrast to IL‐1, IL‐2 does not stimulate cultured hypothalamus cells to synthesize PGE2, and, furthermore, IL‐2 does not elevate serum C‐reactive protein levels. These results predict that the administration of IL‐2 to patients in doses that stimulate cellular immune function will not induce fever and other toxic side effects frequently seen in individuals receiving IFN.