This study was performed to determine the clinical significance of mutations in the EGFR (epidermal growth factor receptor) along with their association with human papillomavirus (HPV) infections in patients with squamous cell carcinoma of the head and neck (HNSCC). Exons 18-21 of the EGFR tyrosine kinase domain were sequenced and HPV typing was carried out using the HPV DNA chip in tissues obtained from patients with tongue and tonsil cancer. Univariate and multivariate analyses were used to identify the significant factors. One hundred and eight patients were enrolled. Ten patients (9%) were HPV positive and 17 (16%) had EGFR mutations. None of the patients with EGFR mutations were HPV positive. Gender, age (<60 years versus 60 years), and smoking history were not associated with EGFR mutations. A higher percentage of patients with tonsillar cancer were HPV positive than those with tongue cancer (26% and 0%, respectively; P<0.001). EGFR mutations were not a significant prognostic factor (P=0.746). HPV-positive patients had prolonged survival (P=0.025). Multivariate analysis revealed a longer overall survival in HPV-positive patients (P=0.007). EGFR mutations are not associated with the HPV-positive status, which may confer a better survival outcome. Clinical features of lung cancer patients with EGFR mutations were not observed in HNSCC. A further study will be needed to confirm these results.