Background and study aims: Gastroparesis patients that have undergone prior intrapyloric Botulinum toxin injection (BTI) may seek an opinion regarding peroral pyloromyotomy (POP). There are only two small reports assessing the role of BTI as a predictor for successful treatment with POP. Patients and methods: We performed a retrospective cohort study to assess whether symptomatic improvement after BTI predicts a response to POP. We included 119 patients who had undergone both BTI and POP at Cleveland Clinic Ohio or Cleveland Clinic Florida from January 2016 to September 2019. Results: 67% of patients had symptomatic improvement to BTI. Gastroparesis Cardinal Symptom Index (GCSI) scores were available in 74 patients with 64% achieving response as defined by a decrease in mean GCSI ≥1. In multivariable analysis, response to BTI (OR 7.7 [95% CI 2.24-26.1]) and higher pre-POP GCSI (OR 2.3 [95% CI 1.2-4.6]) were found to be independent predictors of POP response Conclusions: Clinical improvement after BTI is a predictor of response to POP in patients with gastroparesis. This information may aid in improving patient selection for POP.