EGFR, p27kip1 and Skp2, have been implicated in human cancer development. We have studied these molecules in a search for molecular markers that may have prognostic value in head and neck squamous cell carcinomas (HNSCC). Tissue samples of 62 patients were collected and immunohistochemical analysis was carried out for p27kip1, Skp2 and EGFR protein evaluation. Western blot analysis of p27kip1 was performed. The p27kip1 expression is frequently down-regulated in HNSCC (44.4%, 20/45 cases). The immunohistochemical analysis showed p27kip1 cytoplasmic retention in 7/38 tumors. Strong Skp2 signals were detected at the invasive edge of the tumor in cells lacking p27kip1 staining. We found a high EGFR staining in 49% (23/47) of the cases. The staining tended to be more frequent in lymph node-positive cases. The dysplastic tissue exhibited no Skp2 immunoreactivity, whereas 51.06% (24/47) of invasive tumors expressed high levels. Of note is that Skp2 overexpression was the only factor that significantly correlated with a shorter overall survival in multivariate analysis (p=0.048). Our results suggest that Skp2 is a useful prognostic marker for HNSCC management.