AIM: To evaluate the role of second mitochondriaderived activator of Caspase (Smac) and cysteinyl asparate specific proteinase 9 (Caspase9), alone and in combination, in predicting preoperative chemoradiotherapy sensitivity in patients with rectal carcinoma by investigating the relationship between the expression of Smac and Caspase9 and the pathologic response in patients who have received preoperative chemoradiotherapy. METHODS: The biopsy specimens before chemoradiotherapy and surgical specimens we r e obt a ined f rom 4 3 c a s e s of r e c t a l adenocarcinoma who received preoperative chemoradiotherapy from July 2008 to June 2013. Immunohistochemical staining was used to test the protein expression levels of Smac and Caspase9, and the relationship between Smac and Caspase9 protein expression levels and postoperative pathological response was analyzed. RESULTS: The effective rate of preoperative chemoradiotherapy was as high as 72.1%, and the pathological complete response rate was 30.2%. The expression of Smac and Caspase9 was altered after chemoradiotherapy (P < 0.001 for both). Their expression levels were significantly downregulated after chemoradiotherapy. The effective rate of preoperative chemoradiotherapy was significantly increased in patients who were positive for Caspase9 protein expression (staining score range, 1 to 8) before chemoradiotherapy (P < 0.05). And the effective rate was further increased when Smac and Caspase9 proteins were both positive (P = 0.0002). The survival analysis indicated that chemoradiotherapy response was correlated with the overall survival, and the survival was significantly longer in the response arm than in the nonresponse arm (P = 0.0193). CONCLUSION: The positive expression of Caspase9 protein in biopsy specimens before chemoradiotherapy can be a marker for sensitivity to radiation and chemotherapy in patients with rectal cancer. Joint detection of Smac and Caspase9 proteins can be more reliable in predicting the sensitivity to preoperative chemoradiotherapy in rectal cancer patients. The response to chemoradiotherapy is a key factor responsible for patients’ prognosis. The joint detection of Smac and Caspase9 can be helpful in screening out patients who are sensitive to preoperative chemoradiation. © 2015 Baishideng Publishing Group Inc. All rights reserved.