Background: The current standard of care in locally advanced rectal cancer is neoadjuvant chemoradiation and R0 resection. An optimal radiation-surgery interval (RSI) has not been established. A small institutional dataset showed RSI > 49 days improved pathologic complete response (pCR) rates and disease free survival. However, in a national dataset, RSI greater than 60 days was associated with increased rates of positive margins and impaired overall survival. Because pCR is associated with improved survival, we used a national database to evaluate the relationship between RSI, pCR and survival after neoadjuvant therapy for rectal cancer. Methods: The NCDB was queried for cases 2004-2013 of AJCC stage II or III rectal adenocarcinoma that underwent neoadjuvant radiation followed by radical resection. We excluded patients with missing and outlier RSI. pCR was defined as ypT0N0M0. Chi-square, univariate, multivariable Cox model, and Cochran-Armitage time trend analyses were performed. Results: 23475 patients were identified. 7901 (33.7%) had RSI ≥60 days. pCR occurred in 1766 (11.3%) of the < 60 group and 1174 (14.9%) of the ≥60 group (p < 0.001). RSI ≥60 days has increased over time, from 22.1% in 2004 to 45.4% in 2013 (p < 0.001), as have pCR rates, from 8.4% in 2004 to 14.2% in 2013 (p < 0.001). Multivariable Cox model of the total cohort showed that RSI ≥60 days (HR = 1.11, 95% CI = 1.04-1.19) and residual disease (HR = 2.04, 95% CI = 1.78-2.34) were associated with increased mortality. Subgroup analysis of patients with pCR showed RSI ≥60 days was not associated with worse survival (HR = 1.07, 95% CI = 0.82-1.41). However, analysis of patients with residual disease showed RSI ≥60 days was associated with worse survival (HR = 1.13, 95% CI = 1.06-1.21). Conclusions: In a large national database, RSI ≥60 days worsens survival in patients who have residual disease after neoadjuvant therapy for locally advanced rectal cancer, while there is no difference in those with pCR. Emphasis should be placed on identifying patients who are unlikely to have pCR and to prioritize resection in these patients within 60 days of completion of chemoradiation.