A wide variety of drugs and substances have the potential to damage the respiratory system by different mechanisms. Clofazimine is an anti-leprosy drug that is normally only prescribed for a few years. It has a very long half-life, and crystalline deposition of the drug in various tissues has been documented. But up to now, no fatalities due to pulmonary damage have been described. We report the case of a patient who took clofazimine for almost 27 years as off-label treatment for Melkersson-Rosenthal syndrome. He suffered from progressive dyspnea, productive cough, and occasional hemoptysis. X-ray and CT of the thoracic organs revealed extensive multilocular, compact, tumor-like infiltrates with central necrosis in both lungs. Pulmonary function tests showed restrictive impairment and manifest hypoxemia. Histology of lung biopsies revealed intense interstitial accumulation of histiocytes and marked deposition of crystalline foreign material. The patient died from progressive respiratory failure. Autopsy revealed crystalline deposition and a histiocytic reaction in many other parenchymal organs. Conclusion: Pulmonary parenchymal deposition of drug crystals is a rare mechanism of drug-induced pulmonary diseases. Long-standing, off-label use of clofazimine may cause severe destruction of the lungs and can be fatal.