The interleukin-1 (IL-l) system possesses two distinct receptors (type I and type II) which, together with the accessory protein, mediate a multitude of responses to IL-la and IL-l@, including fever. So far, no receptor subtype-specific ligands have been described. Since both types of IL-l receptors occur in the thermoregulatory areas it was unclear which IL-l receptor type mediates fever. We report here that for a series of deletion mutants of human recombinant IL-lb (hrIL-l/I), the affinity of these ligands for the type I IL-1 receptor correlates with their efficacy to evoke the fever response (hrIL-l/I>des-SND 52-54>des-QGE48-50>des-156). Thus, the results suggest that agonist occupancy of the type I IL-l receptor is essential for IL-l/I-mediated fever.