Purpose: To estimate the rate of pathologic complete response (pCR) after neoadjuvant chemotherapy/(re)chemoradiation and its impact on survival in locally recurrent rectal cancer (LRRC) and to identify predictors of pCR or differences between neoadjuvant treatments. Methods: Among 394 LRRC patients treated at the National Cancer Institute of Milan (Italy), 74 (27.8%) were treated with neoadjuvant chemotherapy with or without (re)chemoradiation before surgery. The pCR rate was estimated, and its impact on 5-year survival was evaluated with the Kaplan–Meier survival method. Univariate analysis was performed to find pre-treatment predictors of pCR. Results: After surgery, in 12 (16.2%) patients, a pCR was observed. All patients who reached pCR had R0 margins after surgery; among the 62 non-pCR patients, R0 margins were obtained in 29 (46.8%) cases only (p = 0.0004). pCR patients showed a significantly higher 5-year overall survival compared to non-pCR cases (33.3% vs. 21.0%, p = 0.045) and a trend toward better 5-year re-local recurrence-free survival. On univariate analysis, no predictor of pCR was found in the present study based on pre-treatment features. Conclusion: Since pCR is significantly associated to R0 resection and 5-year overall survival, pCR could be a target for LRRC cure. However, pCR is currently unpredictable based on pre-treatment features. [ABSTRACT FROM AUTHOR]