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Empyema is a serious complication of pneumonia and has been reported to have a mortality rate of 8.7%. For methicillin-resistant Staphylococcus aureus (MRSA) empyema, treatment includes drainage and specific antibiotics such as vancomycin and linezolid. Strikingly, there are increasing incidences of empyema refractory to vancomycin and linezolid. Despite being inactivated in the lung parenchyma by pulmonary surfactant, daptomycin can penetrate the pleural space and may be better at treating MRSA empyema than vancomycin and linezolid. Some case reports have shown that daptomycin has been used to successfully treat MRSA empyema refractory to linezolid and vancomycin-resistant enterococcus (VRE) empyema. Here, we present a 26-year-old male with a past medical history of intravenous (IV) drug use, newly diagnosed HIV, HCV, and multifocal pneumonia complicated by a left-sided MRSA empyema that partially resolved with vancomycin and drainage. However, he subsequently developed a right-sided loculated pleural effusion. After the patient was switched to daptomycin with continued drainage, the right and left pleural effusions improved significantly. Once medically stable, he was discharged to a rehabilitation facility for further recovery. Our case report demonstrates that daptomycin could be considered as an effective treatment for MRSA empyema, particularly when refractory to vancomycin.