BACKGROUND: Preoperative chemoradiation is the standard treatment for locally advanced rectal cancer. However, it is uncertain whether pretreatment clinical stage, degree of response to neoadjuvant treatment, or pathologic stage is the most reliable predictor of outcome. This study compared various staging elements and treatment-related variables to identify which factors or combination of factors reliably prognosticates disease-free survival in rectal cancer patients receiving neoadjuvant combined modality therapy. METHODS: From a prospectively maintained single institution database, 342 consecutive patients with locally advanced rectal cancer staged by endorectal ultrasound were identified. Patients underwent rectal resection 4 to 8 weeks after a 5.5-week course of pelvic radiotherapy/concurrent chemotherapy. The degree of tumor regression was histologically graded on each resected specimen using a previously reported response scale of 0% to 100%. Predictive models of disease-free survival were created utilizing available pretherapy and postoperative staging elements in addition to the degree of tumor regression noted histologically. Model accuracy was measured and compared by concordance index, with 95% confidence interval (CI). RESULTS: Stratifying patients by degree of tumor regression predicted outcome with a concordance index of 0.65 (95% CI, 0.59-0.71), which was significantly better than models using preoperative stage elements (concordance index of 0.54; 95% CI, 0.50-0.58). However, the model found to be most predictive of disease-free survival stratified patients by final pathologic T classification and N classification elements, with a concordance index of 0.75 (95% CI, 0.70-0.80). CONCLUSIONS: Tumor response to preoperative therapy is a strong predictor of disease-free survival. However, outcome is most accurately estimated by final pathologic stage, which is influenced by both preoperative stage and response to therapy.