To investigate the clinical significance of p53 and p21WAF1/CIP1 in the advanced squamous cell carcinoma (SCC) of the pyriform sinus, we performed immunohistochemical staining of p53 and p21WAF1/CIP1 on the biopsy specimens from patients with stage III or stage IV SCC of the pyriform sinus. The results were compared with clinico-pathological features, including age, histological grade, TNM classification, number of neck lymph node metastases on histopathological examination (pLN) and prognosis. Specific staining for p53 and p21WAF1/CIP1 was detected in 36% and 32% of the specimens, respectively. Positive staining of p21WAF1/CIP1 was observed not only in the p53-negative specimens but also in the p53-positive specimens. Age (p < 0.05) and pLN (p < 0.001) were regarded as the significant prognostic factors. The 5-year survival rate of the p53-positive patients (55%) was significantly higher than that of the p53-negative patients (26.5%: p < 0.03). However, there is no significant difference between the p53 groups after controlling pLN. Although it was not statistically significant, the 5-year survival rate of the p21WAF1/CIP1-positive patients (58.8%) was higher than that of the p21WAF1/CIP1-negative patients (26.9%). These results suggest that expressions of p53 and p21WAF1/CIP1 are independent genetic alterations that may play different roles in the SCC of the pyriform sinus. Expression of p53 could not be regarded as an independent prognostic factor at this point. Further studies including the molecular biological analysis should be performed in order to determine the clinical role of p21WAF1/CIP1.