Treatment results of locally advanced rectal cancer without preoperative chemoradiotherapy (CRT) in Japan do not differ from those of Western countries. Preoperative CRT with new anticancer agents may decrease local recurrence rate and prevent distant metastases, thus improving survival. We conducted a trial to evaluate feasibility of neoadjuvant CRT using S-1 in patients with locally advanced rectal cancer. A multi-institutional (17 specialized centres), interventional, phase II trial was conducted from April 2009 to August 2011. Patients fulfilling the following requirements before neoadjuvant CRT were included: histologically proven rectal carcinoma; tumour in the upper or lower rectum; cancer classified as T3-4 N0-3 M0. Neoadjuvant CRT with S-1 (80 mg/m/day on days 1-5, 8-12, 22-26, and 29-33) and irradiation (total 45 Gy/25 fr, 1.8 Gy/day, on days 1-5, 8-12, 15-19, 22-26, and 29-33) was performed. Total mesorectal excision with D3 lymphadenectomy was performed during weeks 4 and 8 after completion of neoadjuvant CRT. The primary endpoint was completion rate of neoadjuvant CRT. Secondary endpoints were response rate to neoadjuvant CRT, short-term clinical outcomes, curative resection rate, and pathologic response (grade 2/3). Of the 37 patients included, 86.5% completed neoadjuvant CRT (95% CI, 75.5-97.5%), and 10.8% (4) experienced an adverse event (grade 3/4). Response rate (RECIST 1.0) was 56.8% (95% CI, 40.8-72.7%), and pathologic response rate was 48.6% (95% CI, 32.5-64.8%). This study demonstrated that neoadjuvant-synchronous S-1+radiotherapy for locally advanced rectal cancer was feasible in terms of pathologic response and adverse events. Registration number: UMIN-CTR, No. C003396.