Transoral incisionless fundoplication (TIF) has been used for endoscopic treatment of gastroesophageal reflux disease (GERD). TIF using the EsophyX device system (EndoGastric Solutions) was designed to create a full-thickness valve at the gastroesophageal junction through the insertion of multiple fasteners; it improves GERD, reduces proton pump inhibitor use, and improves quality of life. Although TIF is effective in select patients, a significant subset of patients undergoing TIF develop persistent or recurrent GERD symptoms and may need antireflux surgery to control the GERD symptoms. We now report a 48-year-old man with chronic GERD unresponsive to medical management. He underwent TIF complicated by esophageal perforation and developed mediastinitis, left pneumothorax, bilateral pleural effusions, and acute respiratory failure. He required chest tube placement and bilateral decortication for treatment of nonresolving empyemas. Additional postmarketing studies are required to assess the safety, efficacy, and clinical outcomes of this novel procedure, and patients undergoing this procedure need close postprocedural follow-up.