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Aggregatibacter aphrophilus is a normal commensal of the human oropharynx and a member of the HACEK group of organisms. This microorganism can cause a wide variety of infections mainly including endocarditis and osteoarticular infections. However, empyema thoracis caused by A. aphrophilus is very rare. The information about this rare disease is very limited. We herein report 2 rare cases having empyema thoracis due to A. aphrophilus. An 88-year-old man with a history of bronchiectasis and periodontitis was admitted for a 2-week history of right lower chest pain, a low-grade fever, and productive cough. Another 51-year-old man with a history of alcoholic liver cirrhosis was admitted with complaint of right chest pain for one week. The cultures of the pleural effusion in both cases were positive for A. aphrophilus which was confirmed by the matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). The former case responded to a 2-week course of intravenous piperacillin/tazobactam. The latter case died from shock and progressive deterioration of liver function. The effective treatment of A. aphrophilus empyema thoracis should comprise (i) accurate causative pathogen identification by conforming with MALDI-TOF MS, (ii) adequate empyema drainage, (iii) appropriate antimicrobial therapy with penicillin/β-lactam inhibitor combinations or the third-generation cephalosporins, and (iv) underlying diseases management especially malignancy and alcoholism.