1. The effects of repeated injections of bacterial lipopolysaccharide (LPS) at 3 day intervals on abdominal temperature and systemic release of tumour necrosis factor alpha (TNF)-like and interleukin-6 (IL-6)-like activity were measured in guinea-pigs. 2. After the third injection of LPS the fever response was significantly attenuated. 3. TNF-like activity (peak 1 h after LPS injection) and IL-6-like activity (peak 3 h after LPS injection) in plasma changed correspondingly, both being significantly reduced after the third and subsequent injections of LPS. 4. The increase of IL-6-like activity in plasma after LPS injection correlated to the febrile change in body temperature. This correlation remained manifest throughout the whole time course of the development of endotoxin tolerance. 5. The reduced production of TNF-like activity after repeated injections of LPS correlated to the attenuation of the fever index, the integration of the thermal response after LPS application. 6. The results support the hypothesis that one component of the development of endotoxin tolerance is reduced production and release of cytokines in response to repeated injections of the same amount of LPS.