Microcystin-LR (MCLR) is a potent hepatotoxin that rapidly produces death in experimental animals. We have shown that cyclosporin A (CsA) can prevent the toxic and lethal effects of MCLR in mice. The LD50 of MCLR in mice is approximately 61 micrograms/kg, and 100 micrograms/kg produces death in 100% of treated mice. The minimum dose of CsA which prevented lethality in mice given 100 micrograms MCLR/kg i.p. was 10 mg/kg. This dose of CsA did not protect mice against higher doses of MCLR. Survival of all mice given 100 micrograms MCLR/kg was achieved if 10 mg CsA/kg was given 0.5-3 h prior to the MCLR but not if the CsA was co-administered or given after the MCLR. The results indicate that CsA effectively protects mice against a lethal dose of MCLR, but that the time of administration and the dose of CsA are critical determinants of the chemoprotective effects.