Differences in weight gain, efficiency of food utilization, glucose tolerance, insulin levels, and adipocyte cellularity were measured when three different diets were fed to lean agouti and obese yellow mice. Sets of adult and weanling agouti (A/a) and yellow (Avy/A)(BALB/c X VY) F1 hybrid mice were fed high-sucrose (HS), 10 percent fat, or regular lab chow (control). Some mice received the diets only after 12 weeks of eating lab chow (adult-fed); others ate the diets from the time of weaning. Since responses of both age groups were similar, only the data from the adult-fed groups are presented. The HS and 10 percent fat diets increased the body weight gain in both A/a and Avy/A adult mice more than the control diet; the HS diet was utilized more efficiently in the lean agouti females causing a slightly higher weight gain, whereas the 10 percent fat and HS diets were used with the same efficiency by the yellow mice. Short-term feeding (3-5 weeks) with the HS and 10 percent fat diets decreased the glucose tolerance of adult yellow but not of agouti mice. The pancreatic insulin response to a glucose load was higher in all mice fed the HS diet, whereas this response was blunted in those on the 10 percent fat diet. In agouti mice the HS and 10 percent diets increased the mean cell diameter of the parametrial adipocytes and deteriorated the glucose oxidation rate in response to insulin compared to the control diet. In the yellow littermates, on the other hand, the test diets decreased the mean cell diameter and also impaired insulin sensitivity of the adipocytes. The decrease of the mean adipocyte size was probably due to an increased number of small cells.