Background <p>The aim of this study is to compare outcomes of POEM for achalasia between those with (PI) or without (NPI) previous disease intervention.</p> Methods <p>Single-center retrospective study of consecutive achalasia patients with or without ≥ 1 prior intervention with pneumatic dilation (PD), Heller myotomy (LHM), and/or Botox injection (BTI) who underwent POEM and had ≥ 6-month follow-up. Baseline testing: Eckardt Score (ES), high-resolution manometry (HRM), and functional lumen imaging probe (FLIP) of the esophagogastric junction (EGJ) at 50-mL distention. Between 6 and 12&#xa0;months after POEM, patients were questioned about daily PPI use and HRM, ES, FLIP, EGD, and pH testing off anti-secretory medications were repeated when possible. Clinical response was defined as follows: ES ≥ 3, EGJ-DI &gt; 2.8&#xa0;mm²/mmHg, and integrated relaxation pressure (IRP) &lt; 15&#xa0;mmHg. GERD was defined as acid exposure time (AET) &gt; 6%. Outcomes were compared between the PI and NPI groups.</p> Results <p>471 patients (mean: 55 ± 19 yrs; 60% M) with type 1 (17%), 2 (72%) or 3 (11%) achalasia with no prior (<i>n</i> = 325) or a prior (<i>n</i> = 126) intervention were identified. The PI group was older (<i>p</i> &lt; 0.001), had a lower baseline ES (<i>p</i> = 0.03), lower IRP (<i>p</i> = 0.001), higher EGJ-DI (<i>p</i> = 0.001), and a longer POEM procedure time (<i>p</i> = 0.001) compared to the NPI group. Mean overall clinical response by ES (95.3%), IRP (86.7%), and EGJ-DI (86.2%), and daily PPI use (30%), esophagitis (65%), and AET &gt; 6% (49%) were similar between the two groups.</p> Conclusion <p>Achalasia patients with previous LES-directed interventions undergoing POEM are older, have lower ES, lower LES pressure/tone, and require longer POEM times compared to those without previous interventions. Prior intervention does not impact the frequency of clinical response, daily PPI use, esophagitis or post-POEM GERD (ClinicalTrials.gov NCT02770859).</p>