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A 62-year-old man with human immunodeficiency virus (HIV) on long-standing highly active antiretroviral therapy presented for 18F-FDG PET/CT evaluation of a pulmonary nodule. The examination showed unusual radiotracer distribution accumulating in the subcutaneous and visceral fat with low cerebral and skeletal muscle uptake. Imaging features were consistent with HIV-associated lipodystrophy, an unsuspected diagnosis that was later confirmed on physical examination. Recognition of HIV-associated lipodystrophy by the nuclear medicine physician is critical as altered biodistribution may affect diagnostic yield or be mistaken for infectious pathology.