We hypothesized that there is reduced efficacy of fluorinated pyrimidines, such as capecitabine, caused by low active folic acid levels induced by vitamin B deficiency, due to proton pump inhibitors (PPIs), and that this can be recovered by the administration of leucovorin (LV). Thus, we retrospectively analyzed the effects of PPIs on adjuvant tegafur-uracil (UFT) plus LV for stage II/III colorectal cancer (CRC). Patients newly diagnosed with stage II/III CRC who underwent curative surgery and received adjuvant UFT/LV therapy between January 2013 and June 2018 were included. The primary endpoint was the difference in relapse-free survival (RFS) between the PPI and non-PPI groups. Data from 396 eligible patients were evaluated, 84 of whom received PPIs. There were 93 relapse events and 57 deaths across the groups. RFS rates at 5 years were 73.8% (95% confidence interval [CI], 62.9-81.9%) and 77.1% (95% CI, 72.0-81.4%) in the PPI and non-PPI groups, respectively. Cox regression analysis showed no significant differences in RFS between the PPI and non-PPI groups (hazard ratio, 1.16; 95% CI, 0.72-1.87; P = 0.539). Our findings suggest that the concomitant use of PPIs does not significantly reduce the efficacy of adjuvant UFT/LV treatment for patients with stage II/III CRC.