Background: Irinotecan is an effective drug for rectal cancer. Early small sample size trials have assessed the addition of irinotecan to standard CRT with fluoropyrimidines in neoadjuvant phase of locally advanced rectal cancer, in which pCR rates varied from 13.7 to 37%. ARISTOTLE trial, a multicentre UK-based phase III trial, will complete recruitment in autumn 2016. However, all patients in case group were prescribed with weekly irinotecan dose of 60mg/m² guided by UGT1A1*28 6/6 and 6/7 genetypes in neoadjuvant chemoradiation. Therefore, this phase III trial was designed to confirm the potential improvement in outcomes seen with the addition of irinotecan to CRT. Methods: Eligible patients are randomly allocated to either radiotherapy 50 Gy with concurrent capecitabine, followed by a cycle of capecitabine and oxaliplatin two weeks after the end of CRT (Control arm) or radiotherapy 50 Gy with concurrent capecitabine and irinotecan, followed by a cycle of capecitabine and irinotecan (Case arm). Capecitabine is prescribed with 825mg/m² The primary end point is ypCR. The hypothesis is to increase ypCR from 12% in the control group to 25% in the case group. To detect such a difference, with alpha = 0.05 (two-tailed) and belta = 0.15, 360 randomly assigned patients are required. Secondary end points are toxicities, surgical complications, local control, progression-free survival and overall survival. Clinical trial information: NCT02605265