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Introduction Developments in targeted molecular therapies have considerably improved patient survival in cancer. Panitumumab is a monoclonal antibody against the epidermal growth factor receptor (EGFR). It is used to treat metastatic colorectal carcinoma. Although panitumumab is well tolerated in most patients, pulmonary toxicity, especially interstitial lung disease (ILD), is a life-threatening condition. The presentation of panitumumab-induced ILD with spontaneous pneumomediastinum and subcutaneous emphysema is rarely reported. Case report We describe a 61-year-old male with metastatic colorectal carcinoma treated with FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) and panitumumab. He presented to our hospital with a complaint of severe dyspnea. On the evaluation of dyspnea, the patient was diagnosed with ILD. Management and outcome After exclusion of other common causes of pneumomediastinum and subcutaneous emphysema, panitumumab was attributed as a cause of ILD. Oxygen therapy via high flow nasal cannula and intravenous methylprednisolone regimen was started. After two weeks, the patient became asymptomatic with the radiologic amelioration. Discussion Panitumumab-induced ILD is associated with a poor prognosis and might occur randomly in one year after the drug administration. The possibility of the disease should be considered on every admission. Early recognition, discontinuation of causative medication, and immediate glucocorticoid therapy are essential to reduce mortality.