Abstract: To investigate the clinical characteristics of second primary oral squamous cancer ( SPOSC ) in nasopharyngeal carcinoma ( NPC ) patients after radiotherapy. The related prognostic factors are also investigated. Methods: Data of 12,121 NPC patients admitted to the Cancer Center of Sun Yat-Sen University during the period January 1990 to December 2005 were retrospectively analyzed. Of these, SPOSC occurred in 36 cases after radiotherapy for NPC. The Kaplan-Meier curve was used to calculate the accumulated survival rate, and multivariate analysis was performed in these patients using the Cox proportional hazard model. Results: Of the 36 SPOSC patients, 21 died during the follow-up. The overall 3, 5, and 10-year survival rates of the 36 patients who underwent SPOSC treatment were 38.9%, 22.2% and 11.1%, respectively. Of the 36 cases, SPOSC in the tongue occurred in 23 cases, SPOSC in the gum were found in 7 cases, and SPOSC in the palate were found in 3 cases. Lesions at the other sites were seen in the remaining 3 cases. The univariate analysis showed that the major prognostic factors influencing the survival of the SPOSC patients were tumor size, N stage, mode of treatment, and clinical TNM staging. The multivariate analysis for risk factors of the positive lymph node was the independent factor affecting the prognosis. Conclusion: There is a high risk of SPOSC in the tongue after radiotherapy of NPC. Tumor size, pathological N stage, and treatment method are the independent factors affecting survival. Vigilance for SPOSC should be maintained for 5 years after radiotherapy of NPC. Our data indicate that early diagnosis and combined therapy, with surgery as the first choice of treatment for SPOSC, may lead to better survival rate and prognosis.