Mycobacterium xenopi is an unusual pathogen and few such cases have been reported in the literature. We report the case of a patient with a sirolimus-based immunosuppressive regimen, who developed lung cavitation. M. xenopi was isolated from the sputum. The patient was treated initially with rifampicin, isoniazid, and pyrazinamide; levofloxacin was added to the treatment regimen after M. xenopi was demonstrated. A possible relationship between sirolimus and M. xenopi infection has been postulated, probably due to the combination of pulmonary toxicity and cellular immunosuppression of rapamycin.