A 73-year-old man, who was receiving treatment for clarithromycin-resistant nontuberculous mycobacterial infection as an outpatient, was experiencing prolonged fever following surgery for prostate cancer in September 2009, with pneumonia emerging in a computed tomography (CT) scan. On further examination, exacerbation of a nontuberculous mycobacterial infection was diagnosed, and we then were going to treat him with ethambutol, isoniazid, amikacin, and rifabutin. After three months of treatment, he had developed fever, dyspnoea, and hypoxia, and a chest CT scan showed diffusely distributed ground-glass opacities. An elevation of KL-6 and SP-D led us to suspect drug-induced pneumonitis, and bronchoalveolar lavage was performed. Fractionation of bronchoalveolar lavage fluid revealed a remarkable elevation in lymphocytes at 83%. When medication was discontinued, fever, ground-glass opacities on CT, and hypoxia improved. After ethambutol and isoniazid, amikacin were administered and rifampicin was given instead of rifabutin, no subsequent exacerbation was observed. The readministration of rifabutin was not trialled to confirm the source of exacerbation, but this pneumonitis was related to no other etiology; thus we diagnosed it as drug-induced pneumonitis caused by rifabutin. To the best of our knowledge, this may be the first case of rifabutin-induced pneumonitis.