Background: Although neoadjuvant chemoradiotherapy achieves low local recurrence rates in locally advanced rectal cancer (LARC), it delays administration of systemic chemotherapy. About 30% of patients still developed distant metastases, which is the main obstacle for improving survival of LARC. Besides, preoperative radiation causes lots of concerns about anal and sexual functions. We aimed to explore the efficacy of preoperative chemotherapy with mFOLFOXIRI in LARC rather than consistent use of chemoradiotherapy. Methods: Patients with fixed cT3 or cT4 rectal cancer evaluated by pelvic MRI participated in this trial. All candidates were to receive 4-6 cycles of mFOLFOXIRI. MRI will be performed to assess clinical responses. Patients with stable/progressive disease were to have radiation before surgery, whereas responders were to have immediate total mesorectal excision (TME). Postoperative radiation was planned if R0 resection was not achieved. Postoperative FOLFOX was recommended. The primary endpoint is the ratio of tumor downstaging to ypT_0-2N₀M₀.The secondary endpoint included pathologic complete response rate, 3-year disease free survival rate and safety. Results: Between August 2014 and September 2016, 83 patients were enrolled and 80 participants had received TME. Three refused surgery after chemotherapy, because the tumor location is too low to perform sphincter-preserving operation. Of 80 patients completing at least 4 cycles of preoperative chemotherapy, two received short-term radiation before TME, and 10 patients underwent long-term chemoradiotherapy after MRI evaluation. The pCR rate of the whole group was 15 of 80 (18.8%) and the tumor downstaging rate was 43.8%. Among patients without chemoradiotherapy, the pCR rate and tumor downstaging were 14.3% and 41.4%, respectively. And the chemo-related toxicity was all tolerable. Conclusions: Neoadjuvant chemotherapy with mFOLFOXIRI and selective radiation does not seem to compromise outcomes in LARC. The result was promising and further phase III study is warranted to validate this experience. Clinical trial information: NCT02217020