Side effects in the treatment of mycosis fungoides with topical nitrogen mustard include allergic contact dermatitis, hyperpigmentation, urticaria, and erythema multiforme-like dermatitis. We reviewed biopsy specimens from 10 patients with mycosis fungoides who were treated with topical nitrogen mustard for 10-76 months. There was no history of oral psoralen with long-wave UV radiation treatment, radiotherapy, or systemic chemotherapy. Control biopsies taken from erythematous or poikilodermatous patches on the trunk or proximal extremities showed epidermal and dermal changes associated with cytologic atypia that were not present before treatment. These changes included slight epidermal hyperplasia with foci of flat rete ridges, atypical keratinocytes with large nuclei, mostly in the lower portion of the epidermis; suprabasal mitotic figures; a few dyskeratotic cells, focal vacuolar alteration of the epidermal basal layer; increased number of slightly enlarged junctional melanocytes; melanophages in the papillary dermis; dilated blood vessels lined by plump, atypical endothelial cells; and large fibroblasts with atypical nuclei. These atypical histologic changes resemble, in part, those described in association with systemic chemotherapeutic agents, such as etoposide, busulfan, and bleomycin. We conclude that topical nitrogen mustard should be added to the list of chemotherapeutic agents that can produce atypical histologic changes in the skin.