Purpose Proton pump inhibitors (PPIs) are one of the most widely used drugs worldwide and are involved in several drug interactions. Recently, several studies have suggested that PPIs may interfere with the efficacy of capecitabine. This study primarily aimed to investigate the effects of PPI intake on the pathologic response rate of patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy with capecitabine. Method A retrospective study was conducted at a French Comprehensive Cancer Center. Patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy followed by surgery were included in the study. Demographic parameters, treatment characteristics, survival data, and PPI intake data were collected. Frequencies and percentages were reported for categorical variables and medians and interquartile ranges for continuous variables. Distribution of variables was compared according to PPI treatment using the chi-square test or Fisher’s exact test for categorical data and nonparametric Wilcoxon tests for continuous variables. Survival data were estimated using the Kaplan–Meier method and compared using the log-rank test. Results In total, 215 patients were included, of whom 135 (62.8%) were men. The PPI intake frequency was 16.1%. The rate of complete pathological response was not significantly lower in patients on PPIs than in those not on PPIs (8.7% vs. 19%, p = 0.36). PPI intake was not associated with a statistically significant decrease in recurrence-free survival (hazard ratio [HR] = 1.26, 95% confidence interval [CI] 0.61–2.60, p = 0.54) or overall survival (HR = 0.95, 95% CI 0.33–2.76, p = 0.93). Conclusion No significant association was observed between PPI co-medication and complete pathological response or survival in patients treated for locally advanced rectal cancer. However, the safety of PPIs could not be confirmed. Further ancillary studies of prospective clinical trials or studies using the Health Data Hub are necessary to explore the effects of PPIs on rectal cancer more accurately.