The present study was designed to examine the effects of different high fat diets on the liver microsomal metabolism of aminopyrine (AMP) and 1,2-dimethylhydrazine (DMH). Male Sprague-Dawley rats were fed either a low fat (5% corn oil) or high fat (20%) diets containing either corn oil, menhaden oil or beef tallow for a period of up to 9 months. Liver microsomes were assayed for N-demethylase activity for both AMP and DMH substrates at 2 weeks, 1, 6 and 9 months of diet only, and also after 1, 2, 5 and 10 DMH treatments (20 mg/kg body weight). The menhaden oil-fed group had consistently higher AMP demethylase activity, which increased up to 6 months and then declined. Beef tallow-fed rats had the highest DMH demethylase activity following DMH, but this decreased by 10 treatments. These data indicate that type and amount of dietary fat affects microsomal metabolism of carcinogens, which may enhance tumor initiation.