Histological specimens from 62 laryngeal and 31 oral carcinomas were immunohistochemically assessed for p53, p21 and p27 proteins; cases with > 10% labelled nuclei were considered as positive. p21 showed higher expression in patients > 65-years-old (P = 0.04), in chemotherapy responders (P = 0.02), and in stage III patients with longer overall survival (P = 0.02), representing the only independent prognostic factor in the multivariate analysis. In addition, stage III patients with p53-/p21+ showed the longest survival whereas those with p53+/p21- tumors showed the shortest overall survival (P = 0.02). A significant influence on the survival of stage III patients was also found for the combinations of p21 and p27 proteins with p21+/p27- imparting the best and p21-/p27+ the worst prognosis (P = 0.04). p27 expression was significantly related to oral cancer specimens (P = 0.04) and to moderate and high tumor grade (P = 0.01). p53 expression was not significantly related to any of the examined clinicopathological characteristics. Our findings indicated that, by functionally promoting apoptosis, p21 seems to play a key role in the successful response to chemotherapy and may be considered as a predictive factor of a better prognosis in stage III patients with head and neck cancers.