AIM To explore the effects of omeprazole on chemoradiotherapy efficacy and tumor recurrence in rectal cancer. METHODS The medical data of 125 rectal cancer patients who received the same neoadjuvant chemoradiotherapy (CRT) followed by surgery were retrospectively collected. Patients who received omeprazole (OME) orally at a dose of 20 mg at least once daily for six days and/or intravenously at 40 mg a day were recognized as eligible OME users (EOU). Otherwise, patients were regarded as non-eligible OME users (non-EOU). Moreover, a preferred OME dose cut-off of 200 mg on tumor recurrence was obtained by receiver operating characteristic (ROC) curves. Patients were divided into two groups: the effective OME group (EOG, OME = 200 mg) and the non-effective OME group (non-EOG, OME < 200 mg). RESULTS The good response rate of CRT efficacy (50.8%) in EOU was significantly increased compared with non-EOU (30.6%) (p = 0.02). The recurrence rate in the EOG was 10.3%, which was significantly lower compared with 31.3% in non-EOG (p = 0.025). The good response rate of CRT efficacy in EOG was 55.2%, which was obviously higher compared with 36.5% in non-EOG, with a significant difference (p = 0.072). Multivariate Cox analysis demonstrated that OME (non-EOG and EOG) was an independent and significant impact factor for DFS (p = 0.048, HR = 0.30, 95% CI: 0.09-0.99). CONCLUSION When applied as an adjuvant drug in cancer treatment for relieving common side effects of chemotherapy, omeprazole has a synergetic effect in improving CRT efficacy and decreasing rectal cancer recurrence.