Background: Chlorambucil is an alkylating agent that preferentially affects B cells over T cells and has been shown to be effective in the treatment of bullous pemphigoid. Objective: Our purpose was to determine whether chlorambucil is effective in the treatment of pemphigus. Methods: We retrospectively reviewed the medical records of 9 patients with pemphigus (7 with pemphigus vulgaris and 2 with pemphigus foliaceus) in whom therapy with other immunosuppressive regimens failed and who were subsequently treated with chlorambucil and prednisone. Results: There was clinical improvement in 6 of 9 patients and a decrease in indirect immunofluoresent antibody titers in 3 of the 5 patients who had titers drawn before and after treatment with chlorambucil. Three of the 9 patients failed treatment with chlorambucil, as evidenced by lack of improvement of lesions. Conclusion: Chlorambucil may be a potential adjuvant therapeutic approach with steroid-sparing effects in patients with pemphigus who have failed treatment with other immunosuppressive regimens.