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Background: The presence of lymph node (LN) metastasis after neoadjuvant chemoradiation therapy (CRT), which does not always correlate with primary tumor response,is the main obstacle to the implementation of CRT followed by local excision or even a watch and wait approach for the treatment of rectal cancer . We investigated whether cancer gene alterations are associated with LN disease status after CRT in rectal cancer patients.Methods: Pre-treatment biopsies were obtained from 127 patients with Stage II/III rectal cancer enrolled in a multi-center prospective Phase II clinical trial. All patients received neoadjuvant CRT followed by total mesorectal excision. Pathologic staging was determined according to AJCC criteria and patients were grouped according to pathologic LN status. Tumor DNA was extracted from pre-treatment biopsies and analyzed by PCR and sequencing for K-ras and p53 gene mutations. Fisher’s Exact Test was performed to assess the association of gene mutation status with LN metastasis after CRT. Results: Overall, 31 (24%) patients had LN metastasis after CRT. p53 and K-ras mutations were detected in 63 (50%) and 47 (37%) patients, respectively; and 23 patients had both mutations. Patients with p53 mutations had an increased risk of LN metastasis compared to patients who had wild-type p53 (33% vs. 13%; p=0.015). However, the detection of K-ras mutation alone or combined with p53 mutation was not associated with LN metastasis after CRT. Conclusions: Our results suggest that detection of mutant p53 may predict LN metastasis after CRT. Therefore, routine p53 genotyping may help guide appropriate therapy in rectal cancer patients undergoing CRT.