Induction chemotherapy has many benefits of in locally advanced rectal cancer (LARC); one of these is the better control of distant failure. Hyperfractionated radiotherapy (HFRT) is new approach still on evaluation in preoperative setting of rectal cancer. We aimed to evaluate the efficacy of induction FOLFOX followed by HFRT in LARC. From September 2011 to December 2013, 27 patients with LARC were enrolled in this prospective, phase I-II study. Induction FOLFOX bolus was given for two cycles followed by HFRT (1.5 Gy twice day for 30 fractions over 3 weeks for a total of 45 Gy). 5-fluorouracil (5-FU) bolus was administrated during first and last 3 days of radiotherapy. Surgical resection was performed in 4-5 weeks further and followed by adjuvant FOLFOX bolus regimen. Twenty-one (77.8 %) patients were males and 22. 2 % of patients were females, and the median age at diagnosis was 46 years. Low sited tumor was the most presenting site (55.6 %). Clinically positive lymph nodes were presented in 70.4 % of patients. Twenty patients (74.1 %) underwent sphincter sparing procedure. Pathological complete response (pCR) was achieved in seven patients (25.9 %). Tumor and nodal downstaging were recorded in (70.3 %) and (42.1 %) of patients, respectively. Acute and late toxicities were in acceptable range. Two-year disease-free survival was 70.2 %, and overall survival was 87.5 %. Induction FOLFOX followed by HFRT and concurrent 5-FU improves pCR in LARC, and this combination was feasible with acceptable toxicity. Further evaluations are mandatory for this new approach.