Serum lipoproteins, body composition, and adipose cholesterol contents of six obese women were studied during and after major weight loss by very-low-calorie diets (VLCDs). Subjects started at 168 ± 11% of ideal body weight, lost 30.3 ± 3.7 kg in 5–7 mo, followed by 2+ mo in weight maintenance. Serum cholesterol fell from a prediet (baseline) value of 5.49 ± 0.32 to 3.62 ± 0.31 mmol/L (P < 0.01) after 1–2 mo of VLCDs (nadir), after which it rose to 5.95 ± 0.36 mmol/ L (peak, P < 0.01 compared with nadir and baseline) as weight loss continued. With weight maintenance, serum cholesterol fell to 4.92 ± 0.34 mmol/L (P < 0.05 compared with peak). Adipose cholesterol content did not change in peripheral (arm and leg) biopsy sites but rose significantly in abdominal adipose tissue with weight loss. We conclude that major weight loss was associated with a late rise in serum cholesterol, possibly from mobilization of adipose cholesterol stores, which resolved when weight loss ceased.