The effect of weight loss on serum triglycerides (TG), and total, HDL, and LDL cholesterol was measured retrospectively over a 9-month period in 14 obese patients who lost at least 90 lbs on a very-low-calorie, nearly fat-free, formula diet of 300-450 cal/day. These measurements were repeated in seven of these patients during the first 3 months of stable weight maintenance. Changes in total, LDL and HDL cholesterol were biphasic during the hypocaloric diet, showing a decrease during the first 3 months, and subsequently approaching or reaching baseline values. No further change occurred in total cholesterol, LDL cholesterol, or HDL cholesterol during the subsequent weight maintenance phase. Triglycerides decreased by the first month of this diet and remained low throughout the entire 9-month period of caloric restriction and during a 3-month period of weight maintenance. Percentage changes in TG and HDL-C during the first 3 months of hypocaloric diet were inversely correlated with their baseline values, those with the highest initial values showing the greatest decrease, and those with the lowest values showing an increase. These results demonstrate the importance of obtaining multiple specimens over time in interpreting the effect of hypocaloric diets on serum lipids.