Objective — to optimize neoadjuvant treatment in terms of toxic reactions and tumor response in patients with rectal cancer and poor prognostic factors. Subject and methods. The investigation enrolled 249 patients with colorectal cancer (cT3—4, cN0—2, cM0—1). The patients were divided into four groups: 1) radiotherapy at a single focal dose of 4 Gy every other day before a cumulative focal dose (CFD) of 40 Gy, followed by surgery 4 weeks later (n=45); 2) daily radiotherapy fractions of 2 Gy for 5 weeks prior to a CFD of 50 Gy during a 120-hour infusion of 5-fluorouracil (5-FU) 500 mg/m2 in combination with leucovarin 20 mg/m2 i.v. bolus before the initiation of radiotherapy and at its end; radical surgery 4—6 weeks later (n=64); 3) the same radiotherapy regimen as in Group 2 when treated with capecitabine 825 mg/m2 twice daily for 5 days a week; surgery 6-8 weeks later (n=67); 4) the radiotherapy regimen as in Group 2; a SFD of 50 Gy when given intravenous oxaliplatin 50 mg/m2 on days 1, 8, 22, and 29 and capecitabine 825 mg/m2 twice daily on days 1—14 and 22—36 of radiation therapy; surgery 8—10 weeks after neoadjuvant therapy (n=73). Results. Toxic neoadjuvant treatment manifestations occurred in 17 (37.6%) patients in Group 1, in 53 (82.8%) in Group 2, in 20 (29.8%) in Group 3, and in 25 (34.2%) in Group 4; the differences were statistically significant (p<0.05). Complete clinical regression, as evidenced by magnetic resonance imaging, was seen in only 3 (4.7%) patients in Group 2, in 12 (18.0%) in Group 3, and in 12 (16.4%) in Group 4. Capecitabine and oxaliplatin + capecitabine versus continuous infusions of 5-FU significantly increased the rates of complete and partial clinical responses (OR 3.929; 95% CI 1.900—8.121; p=0.0002). Conclusion. When choosing neoadjuvant therapy for patients with locally advanced rectal cancer, the results of the comparative study have made it possible to give preference to radiation therapy, by prescribing capecitabine, and, when regional lymph nodes are substantially affected by tumor, by using oxaliplatin + capecitabine.