A 52-year-old man developed interstitial pneumonitis during treatment with desvenlafaxine for major depressive disorder. The man received desvenlafaxine at 50 mg for symptoms of depression 4 years earlier. Six months after a dose increase to 100 mg, he developed bronchitic symptoms with mild, persistent dyspnea. Investigations revealed a restrictive pattern on pulmonary function testing, bilateral upper lobe reticular opacities with traction bronchiectasis on radiology imaging, and end-stage interstitial fibrosis with honeycomb changes consistent with chronic hypersensitivity pneumonitis on open lung biopsy. He was diagnosed with drug-induced interstitial pneumonitis. Desvenlafaxine was discontinued and the patient received prednisone and mycophenolate mofetil. The patient had subsequent stability in the progression of his pulmonary disease after 1 month. After 1 year of drug discontinuation and treatment, his disease process remained, but without major progression. A Naranjo assessment score of 4 was obtained, indicating a possible relationship between the patient's adverse drug reaction and his use of the suspect drug.