Background: Despite optimal treatment sequence are still challenging, Neoadjuvant chemotherapy (NAC) followed by chemoradiotherapy (CRT) in patients with local rectal cancer (LRC), known as total neoadjuvant therapy (TNT), offers early treatment of micrometastases, with optimal exposure to systemic chemotherapy (CT) and rapid relief of local symptoms. In one hand, Nal-IRI has demonstrated efficacy and safety in the treatment of GI tumors. On the other hand, Watch and Wait (W&W) protocol is currently being imposed as an alternative to surgery in selected patients with LCR who achieve complete clinical response (cCR), offering the possibility of a rectum preservation strategy without the need to surgical intervention. Accordingly, TNT with NAC Nal-IRI, 5-FU, Oxaliplatin (NALIRINOX) could help to increase cCR rates in LRC treatment, allowing to enter W&W protocol. Methods: We performed a national, single arm, multicenter phase II study of patients with LRC treated with biweekly NAC NALIRINOX for 8 cycles followed by CRT. Main inclusion criteria were patients with confirmed histopathological diagnosis of LRC, good performance status and candidates for W&W protocol. Primary objective was the % of cCR rate obtained. Secondary objective was safety profile of NAC NALIRINOX combination. The first reassessment was carried out at 10 +/- 2 weeks after finish CRT, with digital rectal examination (DRE), pelvic MRI, CT body scan and rectoscopy. The results were evaluated and discussed by the multidisciplinary gastrointestinal Tumors Board (including Radiological Oncology, Medical Oncology, Surgery, Gastroenterology, Nuclear Medicine, Radiology and Pathology Departments) If patient achieved cCR, was included in W&W protocol with close follow-up with the same tests. Results: 30 subjects with LRC were recruited between March 2019 and July 2020 (22 men and 8 women); 26 (86.7%) subjects received 8 NAC NALIRINOX cycles. 1 subject received only 1 cycle, 2 subjects received 3 cycles and 1 received 7 cycles. A total of 25 (83.3%) subjects were evaluated for either W&W or surgery after CRT. 10 of them (45.5%) underwent surgery: 5 (50%) Low anterior resection (LAR) and 4 (40%) Abdominoperineal resection (APR). Therefore, 12 (54.5%) obtained cCR after first reassessment and underwent W&W protocol surveillance. Regarding safety endpoint, 6 (20%) subjects reported at least one grade 3 CTCAE toxicity related to any of the NALIRINOX medications. Diarrhea was the most frequent (13.3%), followed by asthenia (3.3%) and decreased appetite (3.3%). All of them had been resolved. Conclusions: TNT with NAC NALIRINOX is a safe and effective therapeutic approach to increase cCR rates and enable to select patients with LRC for W&W protocols Clinical trial information: NCT04009876.