Background/aim Neoadjuvant chemotherapy without radiation (NAC) shows favorable outcomes for locally advanced rectal cancer (LARC), however, the optimal regimen has not been determined yet. This study aimed to compare the efficacy and safety of oxaliplatin, irinotecan, folinic acid, and 5-fluorouracil (mFOLFOXIRI) with capecitabine/S-1 and oxaliplatin (XELOX/SOX) in rectal cancer patients. Patients and methods We retrospectively examined patients with LARC who received mFOLFOXIRI or XELOX/SOX as NAC. Results Between January 2015 and July 2019, 49 patients received mFOLFOXIRI and 37 patients received XELOX/SOX. The pathological response rates (over two-thirds affected tumor area) were 36.7% and 40.5% in the mFOLFOXIRI and XELOX/SOX groups, respectively. Grade 3/4 neutropenia was experienced by 45.0% of the patients in the mFOLFOXIRI group and 8.0% in the XEOX/SOX group. Conclusion Although pathological responses were comparable between two groups, mFOLFOXIRI tended to be more toxic compared to XELOX/SOX as NAC for LARC.