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Abstract Background & Aims The recently developed technique of per-oral endoscopic myotomy (POEM) has been shown to be effective for the therapy of esophageal motility disorders. Limited information is available about POEM adverse events (AE). Methods POEM was performed with the patients under general anesthesia in 241 patients (58% male, mean age 47.4 ± 16.4 years) during 61 months. Main outcome was the rate of intra- and post-procedural adverse events (AE). Post-procedural checks comprised clinical and laboratory examination, and endoscopy, with further follow-ups being performed at 3, 6 and 12 months, respectively. Results 238 out of 241 procedures (mean procedure time 100.2± 39.5 min) were successfully completed. Reasons for abortion were excessive submucosal fibrosis preventing submucosal tunneling. 3 patients had severe procedural-related adverse events (SAE rate 1.2%); one case of pneumothorax requiring intraprocedural drainage, and two patients with delayed SAE (one ischemic gastric cardia perforation and one hemothorax, both leading to surgery). The overall rate of minor AE was 31.1%, mainly prolonged intraprocedural bleeding (>15 minutes hemostasis) and defects of the mucosa overlying the tunnel; none of them led to clinically relevant signs or symptoms. Patients experiencing any AE had a significant prolonged hospital stay (p=0.037) and a trend toward prolonged procedure time (p=0.094). Neck/upper thoracic emphysema and free abdominal air were noted in 31.5% and 35.7% (95.3% drained), but without relevant sequelae. Conclusions POEM has a low rate of serious adverse events; minor adverse events are more frequent but lack a consistent definition. Therefore, based on our experience and literature analysis, we suggest a classification of AE for POEM.