Interstitial lung disease has been reported in association with numerous alkylating agents and other chemotherapeutic drugs. Chlorambucil has only rarely been implicated in this complication. We report a case of a 74-year-old man with chronic lymphocytic leukemia who received high-dose intermittent chlorambucil and prednisone every two weeks. Following several of these courses of therapy, respiratory distress occurred 9 to 12 days after the chlorambucil was given. During the final episode, open lung biopsy was performed and demonstrated typical changes of drug-induced pneumonitis, with interstitial infiltrates and fibrosis and proliferation of type II alveolar lining cells.