BACKGROUND: Cellulite occurs to varying degrees on the thighs and buttocks of many otherwise healthy women. Among the many purported treatments for cellulite, only a handful have been tested in clinical trials. OBJECTIVE: The aim of this study was to critically explore the reputed effect of topical retinol in the treatment of cellulite. MATERIALS AND METHODS: The study compared the effect of topical retinol to a placebo formulation in a left-right randomized trial in order to eliminate the massage-effect. The study was conducted in 15 women aged from 26 to 44 years who had requested liposuction to improve mild to moderate cellulite. RESULTS: After 6-months of treatment, skin elasticity was increased by 10.7% while viscosity was decreased by 15.8% at the retinol-treated site. Such an effect on the tensile properties of skin was more prominent where the mattress phenomenon was the only evidence of cellulite. The lumpy-bumpy appearance of the skin showed either little response or was not responsive to the treatment. Although gross microanatomical differences were not disclosed between the comparative sites at completion of the study, evidence for a shift in the phenotype of connective tissue cells was obtained. The main retinol-related change consisted of a 2- to 5-fold increase in the number of factor XIIIa+ dendrocytes both in the dermis and fibrous strands of the hypodermis. CONCLUSIONS: We hypothesize that the functional and phenotypic changes seen in this study were linked and represent the result of a direct or indirect modulating effect of retinol on cellulite. Such features ultimately improve the resting tensions inside the skin which should in turn smooth the skin surface.