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Background: Peroral esophageal myotomy (POEM) is a novel endoscopic operation for the treatment of achalasia. The operator learning curve for POEM and patient factors associated with operative difficulty are not known. Methods: A single-institution prospective POEM outcomes database was analyzed. All POEM procedures were performed conjointly by the same two surgeons. Associations between preoperative patient variables (series case number, gender, age, BMI, ASA class, prior treatment with dilation or Botox, symptom duration, manometric pressures, achalasia subtype) and operative outcomes (procedure time, tunnel length, myotomy length, number of clips used for closure, EBL, mucosal perforation, need to decompress pneumoperitoneum) were tested using bivariate linear correlation. To assess for changes in efficiency over the course of the series, the total procedure time and the time required for each individual procedural step (submucosal access, tunnel creation, myotomy, and mucosal closure) were tested for best fit to linear, logarithmic, and exponential regression curves using case number as the dependent variable. A subgroup analysis of treatment-naïve patients was secondarily performed. Results: 30 patients underwent POEM, of which 26 were treatment-naïve. Preoperative symptom duration was positively associated with increased operative time (r^2=.55, p<.01). Prior achalasia treatment and EGJ resting pressure were both positively associated with operative time at a trend level (p=.08 for both). Case number correlated negatively with the number of clips required for closure (r^2=-.51, p<.01), whereas duration of symptoms was positively correlated with clip number (r^2=.40, p<.05). Case number correlated negatively, whereas duration of symptoms correlated positively, with occurrence of a mucosal perforation, both at a trend level (p=.06 and .07). Myotomy length proximal to the EGJ increased over the course of the series (r^2=.44, p=.02), whereas there was no change in myotomy length distal to the EGJ. Total procedure time and time to perform tunnel creation, myotomy and mucosal closure did not change over the course of the series. Submucosal access time decreased over the course of the series (r^2=.22, p<.01) with best fit to a logarithmic curve. In treatment-naïve patients only, mucosal closure time decreased over the series (r^2=.17, p=.03) with best fit to an exponential curve. Conclusions: In this POEM series, the time needed to access the submucosa and the number of clips required to close the mucosotomy both decreased with experience. Myotomy length proximal to the EGJ increased with experience. Total procedure time did not change over the course of the series, and may not be an important marker of procedural skill for POEM. Longer symptom duration and prior endoscopic treatment may result in increased operative difficulty.