We report two cases of empyema as a complication of the percutaneous instillation of antifungal drugs for pulmonary and pleural aspergillosis. Case 1 underwent percutaneous administration of amphotericin B and fluconazole for 2 months. Six months later, the patient was found to have an Aspergillus empyema with a bronchopleural fistula. Case 2 with pulmonary and pleural aspergillosis underwent percutaneous administration of amphotericin B for one month. Four months later, the patient underwent pleural drainage due to empyema. Pleural biopsy revealed pleural aspergillosis. In both cases, it was suggested that the preceding Aspergillus infection and percutaneous instillation of antifungals resulted in the development of empyema.