Background: The preliminary results of the OPRA trial demonstrated that a substantial number of patients with locally advanced rectal cancer treated with total neoadjuvant therapy (TNT) could achieve organ preservation. Although most tumor regrowths seem to occur within the first 3 years, longer follow-up is needed to assess the ongoing risk of regrowth. Here, we report the long-term organ preservation rate and oncologic outcomes of the OPRA trial. Methods: A prospective, multi-institutional phase II trial, in which patients with stage II or III rectal cancer were randomized to receive either induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients underwent reassessment for treatment response 8-12 weeks after TNT. Patients who achieved a complete or near-complete response after finishing TNT were offered a watch and wait approach (WW). Those with incomplete response were recommended total mesorectal excision (TME). We report 5-year disease-free survival (DFS), organ preservation (defined as TME-free survival), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival (OS) for each treatment group. We also compared DFS between patients who underwent upfront TME after restaging and patients who underwent TME after tumor regrowth. All analyses followed the intention-to-treat principle and groups were compared using the log-rank test. Results: Of the 324 patients randomized, 158 were assigned to the INCT-CRT group and 166 to the CRT-CNCT group. Median follow-up was 56 months; 85 DFS events were observed. The rates of 3- and 5-year DFS, TME-free survival, LRFS, DMFS and OS are listed in the Table. In total, 80 of the 225 (36%) patients who started WW developed a regrowth; 94% occurred within 2 years and 99% occurred within 3 years. The rate of TME-free survival at 5 years was significantly higher for CRT-CNCT (54%) than in INCT-CRT (39%). 5-year DFS was similar for patients who underwent TME after restaging (61%) compared to patients who underwent TME after regrowth (62%, p = 0.86). Conclusions: In patients with rectal cancer treated with TNT and WW, the majority of tumor regrowths occur in the first 2 years, and regrowth after 3 years is vanishingly rare. Salvage TME for tumor regrowth during WW appears to offer similar outcome to immediate TME after incomplete response to TNT. Distant metastases remain the most frequent cause of treatment failure, with similar rates in the two treatment groups. Clinical trial information: NCT02008656.