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BACKGROUND AND AIMS Peroral endoscopic myotomy (POEM) has become the mainstay for the treatment of achalasia at many institutions around the world since its inception in 2008. POEM can be performed using either the anterior or the posterior approach. The primary aim of this study was to compare the efficacy of the anterior and posterior approaches at 1year after POEM. PATIENTS AND METHODS This is a single-blinded, randomized, non-inferiority international clinical trial. Eligible participants were adult patients with a confirmed diagnosis of achalasia via high-resolution esophageal manometry. Patients were randomly allocated with a 1:1 ratio to receive POEM with anterior or posterior approach. The primary aim was to compare the rate of clinical success (Eckardt score <3) of anterior and posterior approaches at 1 year. RESULTS A total of 150 patients were randomized to receive either anterior (n= 73) or posterior (n= 77) POEM. A total of 148 patients received the POEM treatment and a total of 138 patients completed the 1-year follow-up and were included in the primary efficacy analysis. Technical success was achieved in 71 (97.3%) patients in the anterior group versus 77 (100%) patients in the posterior group (p=0.23). The median (interquartile range) length of hospital stay after the procedure was 2 (1-3) days for both groups. Adverse events occurred in a total of 15 (10%) patients (8 patients (11%) in the anterior group and 7 patients (9%) in the posterior group; p=0.703). Clinical success was achieved in 90% of patients in the anterior group and 89% of patients in the posterior group. Abnormal esophageal acid exposure was detected in 29 out of 59 (49%) and 25 out of 60 (42%) patients in the anterior and posterior groups, respectively, (p=0.67). GERDQ scores were also not significantly different between the study groups. In both groups, quality of life improved after POEM for all SF-36 measures and was similar between both groups. CONCLUSIONS Posterior myotomy during POEM was not inferior to anterior myotomy in terms of efficacy and safety in the treatment of patients with achalasia. (NCT02454335).