Blastomycosis is endemic in river valley areas of the southeastern and Midwestern United States. Pulmonary manifestations include chronic cough and pleuritic pain. Radiographic appearance of the infection can mimic bronchogenic lung carcinoma. Pleural effusion is rarely associated with this pulmonary infection, and empyema has not been previously reported. We report a case of pulmonary and pleural Blastomyces dermatitidis infection presenting as empyema thoracis. Diagnosis and treatment were attained with video-assisted thoracoscopic (VATS) pleural and lung biopsy and debridement.