Background: Neoadjuvant chemotherapy for locally advanced rectal cancer is required to achieve tumor reduction when skipping routine use of preoperative radiation therapy. It is known that EGFR inhibitor has impact on early tumor shrinkage in metastatic colorectal cancer. We evaluated the effect of preoperative infusional fluorouracil, leucovolin, and oxaliplatin (FOLFOX) with panitumumab. Methods: Forty-three patients with clinical stage III rectal cancer without invasion to other organs were enrolled in this multicenter phase II trial. All patients had KRAS wild tumors confirmed by biopsy. Patients received six cycles of FOLFOX with panitumumab. Reduction rate of primary tumor was measured by T2 weighted sagittal image of magnetic resonance imaging. Excluding patients whose disease progressed after the six cycles, total mesorectal excision was performed two weeks after neoadjuvant chemotherapy. After surgery, adjuvant chemotherapy with six cycles of FOLFOX without panitumumab was planned before diverting stoma closure. The primary outcome was the response rate of the primary lesion. Results: Between January 2012 and December 2014, 42 out of 43 patients completed preoperative chemotherapy; one patient did not complete the regimen due to grade III neutropenia. There was no progressive disease in the 42 patients and response rate was 69.8% in this series. Average reduction rate of the primary lesion was 47.6%. All of the 43 participants had R0 resections without mortality or severe complications. Pathological complete response rate to chemotherapy was 7.0% (3 of 43). Thirty-eight out of 43 patients started adjuvant chemotherapy and 32 patients completed the regimen. Grade 3 or worse peripheral neuropathy was not seen during neoadjuvant chemotherapy and seen in 2.6% (1 of 38) during adjuvant chemotherapy. Conclusions: Periopative chemotherapy using FOLFOX with panitumumab seemed to have two advantages; one is tumor reduction which enables skipping neoadjuvant radiation therapy, the other is safely administering a larger dose of chemotherapy than adjuvant only in locally advanced rectal cancer. Additional impact of EGFR inhibitor should be followed in long term results. Clinical trial information: UMIN000006039.