Eight of ten patients with chronic or subacute cutaneous lupus erythematosus completed 16 weeks of oral isotretinoin therapy (80 mg/day). All eight patients noted an excellent clinical response without significant side effects. (Two patients did not return to initial two-week follow-up.) Peripheral blood B- and T-cell counts were unaffected by therapy. Therapy was associated with resolution of routine histopathologic abnormalities, conversion of abnormal lesional direct immunofluorescence microscopy to normal, normalization of the epidermis on electron microscopy, and reduction of all T cells near the dermoepidermal junction without change in ratio of T-helper/inducer cells to T-suppressor/cytotoxic cells. Isotretinoin is a clinically effective short-term therapy for chronic or possibly for subacute cutaneous lupus erythematosus. The primary mechanism of action remains unestablished.