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Background After the first case of per-oral endoscopic myotomy (POEM) at our institution in 2008, the procedure was quickly accepted as an alternative to surgical myotomy and is now established as an excellent treatment option for achalasia. This study aimed to examine the safety and outcomes of POEM at our institution. Study Design Per-oral endoscopic myotomy was performed on 500 consecutive achalasia patients at our institution between September 2008 and November 2013. A review of prospectively collected data was conducted, including procedure time, myotomy location and length, adverse events, and patient data with short- (2 months) and long-term (1 and 3 years) follow-up. Results Per-oral endoscopic myotomy was successfully completed in all patients, with adverse events observed in 3.2%. Two months post-POEM, significant reductions in symptom scores (Eckardt score 6.0 ± 3.0 vs 1.0 ± 2.0, p < 0.0001) and lower esophageal sphincter (LES) pressures (25.4 ± 17.1 vs 13.4 ± 5.9 mmHg, p < 0.0001) were achieved, and this persisted at 3 years post-POEM. Gastroesophageal reflux was seen in 16.8% of patients at 2 months and 21.3% at 3-year follow-up. Conclusions Per-oral endoscopic myotomy was successfully completed in all cases, even when extended indications (extremes of age, previous interventions, or sigmoid esophagus) were used. Adverse events were rare (3.2%), and there were no mortalities. Significant improvements in Eckardt scores and LES pressures were seen at 2 months, 1 year, and 3 years post-POEM. Based on our large series, POEM is a safe and effective treatment for achalasia; there are relatively few contraindications, and the procedure may be used as either first- or second-line therapy. [ABSTRACT FROM AUTHOR]