Obesity is often associated with an elevated total body cholesterol synthesis. In order to evaluate the role of hepatic cholesterogenesis in this phenomenon, we assayed the rate-limiting step in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in the microsomal fraction of liver biopsies obtained operatively from ten morbidly obese (relative body weight greater than 155%) subjects. Eighteen normal-weight patients (relative body weight less than 120%) with cholesterol gallstones served as controls. Hepatic HMG CoA reductase activity, expressed as pmol X min-1 X mg protein-1, was 60% higher in the obese subjects compared to the gallstone patients (P less than 0.05). Microsomal protein concentration was lower in the obese patients, so that enzyme activity calculated per gram liver was not significantly different between the two groups. However, mevalonate formation, expressed in terms of total organ activity, was higher in the obese than in the nonobese group. The results suggest that the liver is a major contributor to the increased cholesterol production seen in obesity.