Abstract Background In recent years, neoadjuvant chemoradiation and subsequent surgical resection with total mesorectal excision has been shown to increase local control with decreased toxicity in comparison to upfront surgical resection followed by adjuvant chemoradiation. Neoadjuvant chemoradiotherapy is the standard treatment for locally advanced rectal cancer. In this study we evaluated the efficacy of adding a selective COX-2 inhibitor to standart neoadjuvant chemoradiation on pathologic response, sphincter preservation and acute toxicity. Materials and Methods Thirty patients with Adenocarcinoma of rectum (up to 15 cm of anal verge) were enrolled in this phase 2 study. Patients undergone full colonoscopy, MRI rectal protocol, abdomino-pelvic and chest CT scan for staging then received neoadjuvant concurrent chemoradiation (capecitabine 825 mg/m2 bid in combination with celecoxib 200 mg bid and radiotherapy (50-50.4Gy/25-28fraction). Surgery was done 5-12 weeks after chemoradiation. Acute complications were scored by common toxicity criteria 5.0 and tumor response was graded according to AJCC and CAP guidelines for rectal adenocarcinoma. Results Of 30 patients, total mesorectal excision was done in 22 patients. Tumor regression grade was reported as: 7 patients (31.8%) had grade 0 or complete response, 7 patients (31.8%) had grade 1 or moderate response, 6 patients (27%) had grade 2 or minimal response and 2 patients (9%) had grade 3 or poor response. Primary tumor down staging was 63% and nodal down staging was 73% with sphincteric preservation rate of 77% among the operated cohort. No patients had hematologic or cardio-vascular toxicity. Conclusion Results indicate celecoxib in combination with neoadjuvant chemoradiation is safe and associated with low toxicity. This combination can promote pathologic complete response, tumor regression grade, sphincteric preservation, T and N down staging in rectal adenocarcinoma.