Interleukin-1 (IL-1) mediates symptoms of sickness during the host response to infection. IL-1 exerts its effects via several subtypes of receptors. To assess the role of IL-1 receptor type I (IL-1RI) in the sickness-inducing effects of IL-1, IL-1β and the cytokine inducer lipopolysaccharide were administered to IL-1RI-deficient mice (IL-1RI–/–). Sickness was assessed by depression of social exploration, anorexia, immobility and body weight loss. IL-1RI–/– mice were resistant to the sickness-inducing effects of IL-1β administered intraperitoneally (2 µg/mouse) and intracerebroventricularly (2 ng/mouse), but still fully responsive to lipopolysaccharide administered intraperitoneally (2.5 µg/mouse) and intracerebroventricularly (3 ng/mouse). The sensitivity of IL-1RI–/– mice to lipopolysaccharide was not due to a higher brain expression of proinflammatory cytokines other than IL-1, since lipopolysaccharide-induced expression of brain IL-1 β, tumour necrosis factor-α (TNF-α) and IL-6 transcripts were identical in IL-1RI–/– and control mice when measured by semiquantitative reverse-transcriptase polymerase chain reaction 1 h after treatment. Blockade of TNF-α action in the brain by intracerebroventricular administration of a fragment of the soluble TNF receptor, TNF binding protein (3.6 µg/mouse), attenuated the depressive effects of intraperitoneal injection of lipopolysaccharide (1 µg/mouse) on behaviour in IL-1RI–/– but not in control mice. Since IL-1RI–/– mice were not more sensitive to intracerebroventricularly TNF-α (50 ng) than control mice, these results indicate that IL-1RI mediates the sickness effect of IL-1 and that TNF-α simply replaces IL-1 when this last cytokine is deficient.