Silicone, commonly used in cosmetic procedures owing to its presumed inertness, can yield serious sequelae including acute embolization and pneumonitis. Chronic pulmonary sequelae in response to silicone injection have not been previously described. We report a case of chronic progressive granulomatous pneumonitis in response to subcutaneous silicone injections in a transgender male-to-female patient infected with human immunodeficiency virus 1 (HIV-1). After receiving silicone injections to the buttock, the patient developed rapid onset dyspnea, pleuritic chest pain, fever, and chills. Chest computed tomography revealed diffuse peripheral interstitial opacities. She responded symptomatically to prednisone with subsequent intermittent symptomatic flares. Four years later, she developed marked dyspnea and cough. Chest computed tomography showed progressive diffuse ground-glass and nodular opacities. Lung biopsies demonstrated numerous spheroid silicone particles within the lung interstitium and small pulmonary vessels, surrounded by foreign body giant cells and nonnecrotizing granulomatous inflammation. We speculate that HIV-1-infected patients may be at risk for chronic, progressive granulomatous pneumonitis due to silicone injection years after their procedure owing to shifting levels of cell-mediated immunity.