Background: In locally advanced rectal cancer in contrast with the conventional approach the administration of chemotherapy prior to chemoradiation (CRT) and surgery allow most patients receive planned treatment with better toxicity profile without compromising the pCR and complete resection rates, as we previously demonstrated. (J Clin Oncol 28:859-865, 2010). We now report on the 5-year outcomes of this randomized trial. Methods: Patients with distal or middle third, T3-T4 and/or N+ rectal adenocarcinoma selected by Magnetic Resonance +/- endorectal ultrasound, were randomly assigned to arm A—preoperative CRT followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)—or arm B— four cycles of CAPOX followed by CRT and surgery. The following five-year outcomes were assessed: the cumulative incidence of local-regional (LRF) and distance failure (DF), disease-free (DFS) and overall (OS) using the Kaplan-Meier method. Results: Of 108 patients accrued, 52 were randomly assigned to arm A and 56 to arm B. According to intention-to-treat analysis with a median follow-up time of 69.5 months, the 5-years DFS rates were 64.3% (95% CI, 49% to 76%) in arm A and 60.7% (95 CI, 46% to 72%) in arm B (P=0.73). The 5-year cumulative incidences of local relapse were 1.9 % and 7.1% in A and B arms respectively (P= 0.36). No significant differences were detected for 5-year cumulative incidence of distant metastases (21.1% and 23.2%; P = 0.80) and 5-years overall survival (77.9% and 74.7%; P= 0.64). Conclusions: Both approaches yield similar 5-y outcomes. Because of the associated acute toxicity sparing and better compliance with induction CT compared with adjuvant CT, integrating effective systemic therapy prior to CRT and surgery may well be the next step in phase III testing versus the standard strategy to capture meaningful differences in DFS.