Objective：This study was aimed to determine whether Melanoma 2（AIM2）expression predicts response to neoadjuvant chemoradiotherapy （nCRT） and outcomes for patients with locally advanced rectal cancer （LARC）. Methods：The study examined the AIM2 expression in 122 pre-treatment biopsies of LARC by immohistochemistry（IHC）. The associations between AIM2 and clinical characters were analyzed. Results：High expression of AIM2 in tumor cells was observed in 26 biopsy specimens. There was no significant correlation between high AIM2 expression in tumor cells and gender（P=0.316），age（P=0.283），differentiation（P=0.356），CEA serum level（P=0.468），tumor location（P=0.309），clinical tumor status（P=0.284），and clinical node status（P=0.264）. There were 65（67.7%） specimens with high expression of AIM2 in 96 postoperative specimens（P < 0.001）. Univariate and multivariate analysis showed that AIM2 high expression in tumor cells could predict LARC resistance to nCRT：25/26（96.2%）cases with AIM2 high expression tumor showed poor response，while 78/96（81.3%）cases with AIM2 low expression tumor showed good response（P < 0.001）. After a median follow-up time of 51 months，multivariate analysis showed that high-expression of AIM2 in tumor cells was not correlated with patients’ recurrence free survival（RFS）（P=0.634）or overall survival（OS）（P=0.932）. Conclusion：AIM2 expression levels might be a useful indicator of nRCT sensitivity for LARC. The administration of AIM2 signaling pathway antagonist may have the potential to increase rectal cancer radiosensitivity.