Primary cardiac synovial sarcoma (PCSS) most commonly originates in the right atrium of the heart and is exceptionally rare. Although biomarkers of autoimmune diseases, such as antinuclear antibodies (ANAs), have been reported as potential indicators of certain tumors, the association between PCSS and ANAs remains unclear. Herein, we describe a case of pleural effusion that was initially considered to be due to connective tissue disease (CTD) but was finally diagnosed as PCSS through endobronchial ultrasound-guided transbronchial mediastinum biopsy (EBUS-TBMB). Clinicians need to update their knowledge regarding the potential association between PCSS and ANAs. This case report also emphasizes the importance of EBUS-TBMB, under the guidance of positron emission tomography/computed tomography (PET/CT), in the diagnosis of this rare tumor in an unusual location.