A 72-year-old male was treated with anti-tuberculosis drugs for pulmonary tuberculosis (rⅢ2). A large volume of right pleural effusion appeared after 2 months. We performed thoracoscopy procedures under local anesthesia for a differential diagnosis. Multiple white nodules were found on the parietal pleura and the biopsy specimen showed epithelioid cell granuloma without caseous necrosis. We diagnosed paradoxical response and continued the anti-tuberculosis therapy. The pleural effusion improved 3 months after treatment. Acid-fast bacterial staining and polymerase chain reaction (PCR) for Mycobacterium tuberculosis were conducted, and bacteria were not detected in the pleural effusion. Furthermore, culture test of the pleural effusion and biopsy specimens of the pleura were negative for bacteria. Based on these findings, it is speculated that an increased immune response to the mycobacteria on the pleura induced granuloma formation and pleural effusion. This is the first case report of paradoxical response on pleural lesions pathologically diagnosed using thoracoscopy under local anesthesia during antimicrobial therapy for pulmonary tuberculosis.