Cyclosporin (Cs), a cyclic nonpolar undecapeptide of fungal origin, has potent immunosuppressive and antiparasitic activities, and renal and hepatic toxicities, the mechanisms of which are not worked out. Many nephrotoxins and hepatotoxins are predictably more or less harmful, depending upon the circadian stage at which they are administered. In order to find treatment schedules that might damage the animal least, the toxicity of 20 mg kg-1 day-1 of Cs given intraperitoneally was studied at six different circadian stages in adult male Lewis rats. Cs toxicity was gauged by body temperature decline, body weight loss, and survival time. Rectal temperatures over a 24-hr span during the 2 days prior to the first death revealed that rats treated during darkness were 1.6 ± 0.3°C cooler than vehicle-treated controls, whereas rats treated during the light span were only 0.4 ± 0.2°C cooler than controls (p < 0.01). Rats treated in darkness lost twice as much weight compared to those treated in light (20 ± 2 versus 10 ± 2%, p < 0.01). Rats receiving daily Cs in the dark span lived an average of 28 ± 5 days compared with 44 ± 4 days for animals getting Cs during the light span (p < 0.05). Three separate nonspecific measures of drug toxicity confirmed that there was substantial circadian stage dependence to Cs toxicity. The safest time for the drug in rats was 2 to 10 hr after lighting onset, a time when rats are usually beginning their diurnal rest and/or sleep span.