A 34-year-old woman with tobacco use disorder, severe obesity, and chronic hypoxemic respiratory failure of unknown cause was referred to the pulmonary clinic for worsening dyspnea and dry cough. She reported no history of environmental or occupational exposures, substance use, or fevers. Her oxygen saturation was 93% while she was receiving 3 liters of supplemental oxygen. On physical examination, breath sounds were quiet but vesicular. There was no clubbing of the fingers. Pulmonary-function tests showed mild restriction and a mild reduction in diffusing capacity. Computed tomography of the chest showed diffuse ground-glass opacities and areas of peripheral consolidation but no basilar reticulations or honeycombing (Panel A). The results of testing for autoantibodies and hypersensitivity pneumonitis were negative, and bronchoalveolar lavage was not diagnostic, so surgical lung biopsy was performed. The histopathological analysis showed interstitial fibrosis and extensive alveolar filling with pigment-laden macrophages on hematoxylin and eosin staining (Panel B, arrows). These findings were consistent with a diagnosis of desquamative interstitial pneumonia, a rare form of idiopathic interstitial pneumonia that is highly associated with cigarette smoking. A lung biopsy is necessary to make the diagnosis. Treatment with a smoking-cessation program and a tapering dose of glucocorticoids was initiated. At the 3-month follow-up, the patient’s symptoms remained unchanged as she continued to engage in smoking cessation.