Background: The expression of P21 and TBX2 in laryngeal squamous cell carcinoma (LSCC) and their corresponding adjacent normal laryngeal tissues, as well as their association with clinical pathological features and survival remain unclear. Method: we used the RT-PCR and immunohistochemistry to detect their mRNA and protein levels in 75 LSCC patients. We also use log-rank test and Cox models to compare survival among different groups. Results: The mRNA expression level of TBX2 was up-regulated, while P21 was down-regulated in LSCC compared with their matched adjacent laryngeal tissues (All P < 0.001). The expression of P21 was correlated with tumor stage, lymph node metastasis and smoking; and TBX2 expression was associated with lymph node metastasis, differentiation degree and smoking (All P < 0.05). Patients with high TBX2 and low P21 expression had significantly worse survival than those with low TBX2 and high P21 expression, respectively (All P < 0.05). A significant correlation between expression of TBX2 and P21 (Pearson, P < 0.05) was observed. Furthermore, multivariable analysis showed that patients with low TBX2 and high P21 expression alone had a significantly reduced risk for overall death compared with those with low TBX2 and high P21 expression. The risk for overall death was even lower for patients with both low and high expression of both genes than any other co-expression status of both genes (HR, 0.1; 95% CI, 0.0-0.9). Conclusion: These results suggest that abnormal expression of P21 and TBX2 in tumors may jointly, or individually, predict poor prognosis of LSCC.