Objective: To investigate the safety and efficacy of oral methylprednisolone combined with azathioprine sodium or mycophenolate mofetil for the treatment of bullous pemphigoid. Design: A prospective, multicenter, randomized, non-blinded clinical trial to compare 2 parallel groups of patients with bullous pemphigoid undergoing different treatments. Setting: Thirteen departments of dermatology in Germany. Patients: Patients with bullous pemphigoid (n=73) as evidenced by clinical lesions suggestive of bullous pemphigoid, signs of subepidermal blistering on histologic analysis of skin biopsy specimens, linear deposition of IgG and C3 along the dermoepidermal junction, and deposition of autoantibodies at the blister roof in split-skin analysis. Interventions: Treatment with oral methylprednisolone plus azathioprine (azathioprine group) or oral methylprednisolone plus mycophenolate mofetil (mycophenolate mofetil group). Main Outcome Measures: The cumulative total methylprednisolone doses and rates of remission. Secondary outcome measures were safety profiles and duration of remission. Results: In 38 of 38 patients in the azathioprine group (100%), complete remission was achieved after a mean±SD of 23.8±18.9 days vs 42.0±55.3 days for 35 of 35 patients in the mycophenolate mofetil group (100%). In the azathioprine group, the median±SD total cumulative methylprednisolone dose used was 4967.0±12 190.7 mg vs 5754.0±9692.8 mg in the mycophenolate mofetil group. Nine of 38 patients in the azathioprine group (24%) experienced grade 3 or 4 adverse effects vs 6 of 35 patients in the mycophenolate mofetil group (17%). Azathioprine therapy induced significantly elevated liver function test results compared with mycophenolate mofetil (P<.001). Importantly, patients in the azathioprine group showed significantly higher toxicity grades for aspartate aminotransferase (P=.03), alanine aminotransferase (P=.03), and γ-glutamyltransferase (P=.01) than did those in the mycophenolate mofetil group. Conclusions: Mycophenolate mofetil or azathioprine demonstrate similar efficacy during treatment of bullous pemphigoid, and similar cumulative corticosteroid doses were given in both treatment arms to control disease. However, mycophenolate mofetil showed a significantly lower liver toxicity profile than azathioprine therapy. Trial Registration: clinicaltrials.gov Identifier: NCT00431119.