The JCR:LA-corpulent rat, if homozygous for the cp gene, exhibits a syndrome characterized by obesity, hypertriglyceridemia, and hyperinsulinemia with impaired glucose tolerance. The insulin and glucose metabolism of lean and obese rats of this strain have been studied with the euglycemic insulin clamp technique in 3- and 9-month-old rats. Lean rats require a twofold greater glucose infusion rate than obese rats at high plasma insulin concentrations. Glucose turnover was measured using isotope dilution techniques and 1-3H-glucose. Glucose turnover in lean rats of both sexes increases by a factor of 2 to 3 at very high insulin levels. In contrast, obese male rats are unable to respond even to extreme insulin levels with an increase in basal glucose turnover, indicating a profound insulin resistance. The calculated hepatic glucose production is inhibited by high insulin levels in the obese male rats, while lean animals show no inhibition. Thus, the obese male rats have normal basal glucose turnover, but have a profound insulin insensitivity in peripheral tissues. These abnormalities are present at a much reduced level in the obese female rats. These results are consistent with the hypothesis that the hyperinsulinemia, which correlates strongly with cardiovascular disease in this strain of rat, is secondary to a marked peripheral insulin resistance.