To evaluate the efficacy of topical application of calcipotriol to healing wounds in preventing or reducing hypertrophic scar formation and to investigate the biochemical properties of the epidermis associated with hypertrophic scar formation. Design: Randomized, double-blind, placebo-controlled trial using the reduction mammoplasty wound-healing model. Setting: University Medical Center Groningen. Patients: Thirty women who underwent bilateral reduction mammoplasty. Interventions: For 3 months, scar segments were treated with either topical calcipotriol or placebo. Main Outcome Measures: Three weeks, 3 months, and 12 months postoperatively, the scars were evaluated and punch biopsy samples were collected for immunohistochemical analysis. Results: No significant difference in the prevalence of hypertrophic scars was observed between the placeboand calcipotriol-treated scars. Only scars with activated keratinocytes 3 weeks postoperatively became hypertrophic (P=.001). Conclusions: Topical application of calcipotriol during the first 3 months of wound healing does not affect the incidence of hypertrophic scar formation. We observed a strong association between keratinocyte activation and hypertrophic scar formation.