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Background. RAS gene mutations have an impact on treatment response and overall prognosis for certain types of cancer. Objectives. To determine the prevalence and impact of K-RAS codons 12 and 13 mutations in patients with locally advanced HNSCC treated with primary or adjuvant chemo-radiation. Methods. 428 consecutive patients were treated with chemo-radiation therapy and followed for a median of 37 months. From these, 199 paraffin embedded biopsy or surgical specimens were retrieved. DNA was isolated and analyzed for K-RAS mutational status. Results. DNA extraction was successful in 197 samples. Of the 197 specimens, 3.5% presented K-RAS codon 12 mutations. For mutated cases and non-mutated cases, complete initial response to chemoradiation therapy was 71 and 73% (P = 0.32). LRC was respectively 32 and 83% (P = 0.03), DFS was 27 and 68% (P = 0.12), distant metastasis-free survival was 100 and 81% (P = 0.30) and OS was 57 and 65% (P = 0.14) at three years. K-Ras codon 13 analysis revealed no mutation. Conclusion. K-RAS codon 12 mutational status, although not associated with a difference in response rate, may influence the failure pattern and the type of therapy offered to patients with HNSCC. Our study did not reveal any mutation of K-RAS codon 13.