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Gynoid lipodystrophy (cellulite) affects most women, and many seek plastic surgery consultation to improve appearance. Various products are offered, but the literature on the cause and treatment is limited. Understanding the biological and biophysical factors that affect severity may facilitate the development of effective therapies. There has been a dramatic increase in the number of people who have lost significant weight as a result of bariatric surgery or medically supervised weight programs. The effect of weight loss on cellulite severity has not been systematically studied and remains a common patient concern. The authors hypothesized that cellulite severity would decrease with weight loss and subsequent decrease in subcutaneous fat in most subjects.The authors examined the cellulite changes in female subjects who were enrolled in medically supervised weight loss programs using quantitative surface roughness by three-dimensional laser surface scanning, tissue composition by dual energy x-ray absorptiometry, dermal-subcutaneous structure with three-dimensional ultrasound, and tissue elasticity with biomechanical measurements.The majority of subjects had an improvement in cellulite with weight loss, but the condition worsened for others. Improvement was associated with significant reductions in weight and percentage of thigh fat, significantly higher starting body mass index, and significantly greater initial severity. Cellulite worsened with a significantly smaller starting body mass index, smaller reductions in weight accompanied by no change in percentage of thigh fat, and significant increases in tissue compliance.Cellulite is a complex condition, and treatments such as weight loss have variable effects on the improvement or worsening of this condition. Additional studies are required to understand how the factors that influence and modulate cellulite severity, particularly those at the level of the subcutaneous tissue septa, can be manipulated to improve this condition.