The potential chronic toxicity and oncogenicity of dimethylacetamide (DMAC) was evaluated by exposing male and female rats and mice to 0, 25, 100, or 350 ppm DMAC for 6 hr/day, 5 days/week for 18 months (mice) or 2 years (rats). Clinical pathology was evaluated at 3, 6, 12, 18, and 24 (rats only) months. An interim euthanization for rats occurred at 12 months and hepatic cell proliferation in rats and mice was examined at 2 weeks and 3 and 12 months. No compound-related effects on survival were observed. Rats exposed to 350 ppm had lower body weight and/or body weight gain. There were no compound-related effects on body weight or weight gain in mice at any concentration. There were no compound-related adverse effects on the incidence of clinical signs of toxicity in rats or mice. No hematologic changes were observed in either species. Serum sorbitol dehydrogenase activity was increased in rats exposed to 350 ppm. Serum cholesterol and glucose concentrations were significantly higher in 100 and 350 ppm female rats. Compound-related morphological changes were observed in the liver. In rats, exposure to 100 or 350 ppm produced increased absolute and/or relative liver weights, hepatic focal cystic degeneration, hepatic peliosis, biliary hyperplasia (350 ppm only), and lipofuscin/hemosiderin accumulation in Kupffer cells. In mice, exposure to 100 or 350 ppm produced increased absolute and relative liver weights (350 ppm females only), accumulation lipofuscin/hemosiderin in Kupffer cells, and centrilobular single cell necrosis. Male rats exposed to 350 ppm also had significantly higher absolute and relative kidney weights which correlated with the gross and microscopic changes resulting from a compound-related increase in severity of chronic progressive nephropathy. Female mice exposed to 350 ppm had an increased incidence of bilateral, diffuse retinal atrophy. No increase in hepatic cell proliferation was seen in mice or rats at any exposure concentration. DMAC was not oncogenic under these experimental conditions in either the rat or mouse. The NOAEL for male and female rats and mice is 25 ppm.