Background: Fluorouracil -based neoadjuvant chemoradiotherapy(CRT) followed by total mesorectal excision and adjuvant chemotherapy is the standard treatment for locally advanced rectal cancer (LARC). Adjvuant FOLFOX improved survival benefit compared with fluorouracil in patients with ypStage II andIII after CRT. However, induction or consolidation chemotherapy with FOLFOX before surgery had been the new standard for LARC. Whether adjuvant chemotherapy with FOLFOX still improves survival outcomes in ypStage III patients previously exposed to oxaliplatin-based treatment was unknwon. Methods: Patients with LARC receiving oxaliplatin-based neoadjuvant treatment from January 2015 to December 2019 were retrospective analyzed. The inclusion criteria included neoadjuvant FOLFOX chemotherapy alone or induction chemotherpay, concurrent FOLFOX and consolidation chemotherapy before CRT. The duration of neoadjuvant oxaliplatin exposure time was less than 4 months. The efficacy of adjvuant FOLFOX chemotherapy was analyzed among these ypStage III patients according to adjuvant chemotherapy cycles after surgery. Results: A total of 227 patients with ypStage III were enrolled, with the 3-year DFS rate of 46.1% (95%Cl 37.3%-54.9%).Among these patients, 193 patients received adjuvant FOLFOX chemotherapy, including 7 patients had ≤ 2 cycles of adjuvant treatment. And 34 patients had observation after surgery. The 3-year DFS rates bewteen FOXFOL adjvuant chemotherapy group and observation group were 44.7% vs. 56.5%, respectively (HR, 1.190, 95%Cl 0.6246-2.267, P= 0.597). Forty-one patients had ≤ 2 cycles of adjuvant treatment. The 3-year DFS was 43.6% vs. 60.4% (P = 0.597) between pateints receiving over 2 cycles of adjvuant chemotherapy and ≤ 2 cycles of treatment. Conclusions: Among ypStage III LARC pateints after neoadjuvant treatment with Oxaliplatin-Based regimen, adjuvant chemotherapy with FOLFOX failed to improved surival benefit. More enhanced regimen might be necessary for these oxalipatin-resistant patients.