Localized scleroderma or morphea, although a self-limited and benign disease, may leave substantial physical and cosmetic deformity necessitating treatment but treatment remains to date unsatisfactory. The aim of our study was to evaluate the efficacy of topical tacrolimus ointment in the treatment of morphea. Thirteen patients with morphea used tacrolimus 0.1% cream b.i.d. without occlusion for 4 months. Patients were followed up for up to a year. A 4-mm biopsy was taken before starting treatment in seven patients and 4 months after continuous use of tacrolimus 0.1% ointment, next to the previous biopsy site. Masson trichrome and elastica stains were performed to evaluate the distribution of elastic fibers as well as the streptavidin-biotin horseradish peroxide immunohistochemical method for the detection of CD20/L-26, CD3, CD8, CD4, CD1a, human leukocyte antigen-DR and CD25. Four patients had a less than 25% improvement, two patients responded by 50-70% and the remaining seven by more than 70%. Patients with thick, well-established lesions responded poorly in comparison to others with less thick and more erythematous ones. Patients with mild-to-moderate fibrosis histologically were more likely to improve after treatment, while the lymphocytic infiltrate decreased regardless of initial degree before treatment. It was concluded that topical tacrolimus 0.1% cream may be used in patients with morphea, particularly with early inflammatory lesions, even as a first-line treatment.