To evaluate the efficacy of systemic immunosuppressive drugs, including corticosteroids, in the long-term treatment of ocular cicatricial pemphigoid, we conducted a prospective clinical trial in 57 patients (34 women and 23 men ranging in age from 46 to 94 years). Each patient was assigned to one of five groups. Group 1 (26 patients) served as the control group (four patients in this group who showed progression were later switched to treatment groups). Group 2 (eight patients) received combination therapy with cyclophosphamide and prednisone; Group 3 (13 patients) received cyclophosphamide alone: Group 4 (nine patients) received azathioprine; and Group 5 (five patients) received prednisone alone. We found that untreated ocular cicatricial pemphigoid has a variable course and does not necessarily progress. Further, the disease may be asymmetric in severity and progression; progression is more likely in advanced stages than in the earlier stages. Although immunosuppressive therapy inhibited conjunctival shrinking in all four treatment groups, some eyes in each group progressed despite treatment. Serious complications included hemorrhagic cystitis, dermatitis, anorexia and weight loss, gastrointestinal bleeding, and leukopenia.