Background. The effect of HPV infection status and ethnic differences on the prognosis of tongue squamous cell carcinoma in Xinjiang presents an interesting set of conditions that has yet to be studied. Methods. A comprehensive analysis of clinical data was undertaken for a cohort consisting of 63 patients with tongue squamous cell carcinoma recruited from three ethnic groups in Xinjiang. PCR was used for the detection of HPV16 and HPV18 infections. Kaplan-Meier survival analysis was used for analyzing survival outcome in addition to the assessment of other prognostic factors. Results. The overall infection rate for HPV was 28.6% (18/63); the 5-year survival rate among the HPV-positive patients was 47.8% and 30.3% for HPV-negative patients. The survival rate for HPV-positive patients who received radiotherapy and chemotherapy was better than for those who did not receive radiotherapy and chemotherapy. N staging and HPV infection were found to be two independent and significant prognostic factors. Conclusion. HPV-positive patients with tongue squamous cell carcinoma are more sensitive to chemotherapy. Higher N staging indicates poor prognosis.