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This study evaluates factors associated with a pathologic complete response (pCR) after neoadjuvant chemoradiation for rectal cancer.Approximately 20% of rectal cancer patients undergoing neoadjuvant chemoradiation achieve pCR, which has been associated with decreased local recurrence and improved recurrence-free survival. Means of predicting pCR remain incompletely defined.A total of 306 consecutive patients with stage II or stage III rectal cancer who underwent neoadjuvant chemoradiation then surgery between 1997 and 2007 were identified from a single-institution. Sixty-four patients with concurrent inflammatory bowel disease, hereditary colorectal cancer, other malignancy, urgent surgery, incomplete chemoradiation, or insufficient data were excluded. All patients received neoadjuvant 5-FU-based chemotherapy and external beam radiation. Histologic response was categorized as pCR or not-pCR, which defined the 2 study cohorts. Variables were analyzed by univariate and multivariate analysis with pCR as the dependent variable. Fisher exact test, χ2, Wilcoxon rank-sum, and logistic regression were used for analysis. P < 0.05 was considered statistically significant.Of the total patients, 242 were studied, including 58 (24%) that achieved pCR. The 2 groups were statistically similar in terms of age, gender, body mass index, tumor differentiation, radiation dose, and pretreatment stage. On multivariate analysis, an interval ≥8 weeks between treatment completion and surgical resection was significantly associated with a higher rate of pCR, which correlated with decreased local recurrence and improved overall survival.Despite traditional beliefs that certain patient and tumor factors influence pCR, an extended interval between completion of neoadjuvant therapy and surgery was the single most important determinant in achieving a pCR.