In a 2-week probe study male and female Fischer-344 rats and B6C3F1 mice were exposed 6 hr/day to 2000, 500, 100, or 0 ppm methyl isobutyl ketone (MIBK). At 2000 ppm there was a slight increase in male rat liver weight (absolute and relative). The only changes observed histologically were increases in regenerative tubular epithelia and hyalin droplets in kidneys of male rats exposed to 2000 or 500 ppm. Exposure levels for a subchronic study were 0, 50, 250, or 1000 ppm methyl isobutyl ketone vapors 6 hr/day, 5 days per week, for 14 weeks. The 14 weeks of exposure had no adverse effect on the clinical health or growth of rats or mice. Male rats and male mice exposed to 1000 ppm MIBK had a slight but statistically significant increase in liver weight and the liver weight/body weight ratio. Liver weight was also increased slightly in male mice exposed to 250 ppm. No gross or microscopic hepatic lesions related to MIBK exposure were observed. Furthermore, the only microscopic change observed was an increase in the incidence and extent of hyalin droplets within proximal tubular cells of the kidneys of male rats exposed to 250 and 1000 ppm of MIBK. The relevance of the male rat kidney tubular effect to humans is not known. In conclusion, other than the male rat kidney effect, exposure of male and female rats and mice to MIBK at levels up to 1000 ppm for 14 weeks was without significant toxicological effect.