A 49-year-old man with a history of recurrent melanoma in the parotid was treated with parotidectomy, external beam radiation, and high-dose interferon-alpha-2b. Combined F-18 fluorodeoxyglucose positron emission tomography and computed tomography (FDG PET/CT) performed for restaging demonstrated multiple bilateral hilar and mediastinal hypermetabolic foci corresponding to hilar and mediastinal lymphadenopathy. Cytologic specimens obtained by bronchoscopy were negative for malignancy, revealing reactive lymph nodes. Subsequent FDG PET/CT showed regression of the findings. Awareness of possible interferon-associated reaction in melanoma patients who undergo FDG PET is important to avoid pitfalls in the interpretation.