Fourty-two patients, presenting with clinically evaluable cutaneous fibrosis after radiotherapy for breast carcinoma, were treated for 3 months by a superoxide dismutase (SOD) topical preparation. Sequential cutaneous punch biopsies were performed before and 3 months after completion of the treatment. The histochemical grading, using an objective spectrometric method, showed a decrease of fibrosis in 74% of treated patients. The immunohistochemical expression of smooth muscle cells (SMC) α-actin, epidermal growth factor-receptor (EGFR) and transforming growth factor β1 (TGFβ1) was studied. SOD treatment resulted in an increase of SMC α-actin expressing fibroblasts in 79% and an increase of EGFR expressing epidermal cells in 67% cases. It did not modify the expression of TGFβ1. In conclusion, topical SOD appeared to reduce collagen accumulation in the dermis of irradiated skin and to ‘reactivate’ cellular functions in dermal fibroblasts and epidermal cells, as demonstrated by phenotypic changes.