The paradox that cholesterol may be lower in extremely obese subjects versus those who are less overweight, although originally observed more than 40 years ago, has never been documented in a systematic fashion. We have therefore prospectively determined the body mass index (BMI) and serum cholesterol concentration in 3,312 women. The percentage of women with serum cholesterol in the normal range (<200 mg/dL) decreased with an increasing BMI, from 55% in women with a BMI less than 20 kg/m2 to 28% in those with a BMI of 30 to 35 kg/m2. Serum cholesterol greater than 300 mg/dL was found in only 2% of individuals with a BMI less than 20 kg/m2 but in 6% of the group with a BMI between 30 and 35 kg/m2. However, among morbidly obese women (BMI >40 kg/m2, n = 46), 39% presented with serum cholesterol less than 200 mg/dL and only one woman had serum cholesterol more than 300 mg/dL. With the BMI, the fitted regression model shows an increase in cholesterol for low BMIs, while cholesterol appears to decrease with larger values for the BMI. The age-dependent increase in cholesterol is more evident in younger women versus older women, where it tends to disappear. It is concluded that among morbidly obese women (BMI >40 kg/m2), there is a substantial subgroup with normal serum cholesterol.