Verrucous carcinoma (VC) is a well-differentiated form of squamous cell carcinoma (SCC) with better prognosis. Differences in molecular pathogenesis between the 2 have not been well-characterized. We conducted this study to evaluate immunohistochemical expression of cell-cycle regulatory proteins p53, pRb, p16, and p27 in SCC and VC, compare the expression in these 2 neoplasms, and assess if these markers have any diagnostic or prognostic value. Sixty cases of SCC with and without lymph node metastasis and 31 cases of VC were studied. Immunohistochemical analysis for p53, pRb, p16, and p27 was performed and the results were analyzed. SCC was most frequent in tongue (52%), whereas VC in buccal mucosa (81%). Mean age of SCC patients was significantly lower than in VC. Majority of SCCs were in stage III and IV (63%), whereas VCs were in stage I and II (84%). p53 immunopositivity was more frequent in SCC (65%) than in VC (23%) (P≤0.001). VC had lower p53 as compared with well-differentiated SCC and SCC without lymph node metastasis. No significant difference was seen in pRb, p16, and p27 expression. Disease-free survival (DFS) at 1 year for SCC was 57% whereas it was 80% for VC (P=0.02). DFS and overall survival of SCC correlated with nodal status and stage; cell-cycle–associated protein expression had no association with DFS. To conclude, p53 immunoexpression differs in SCC and VC, suggesting different pathogenesis, and it may have some utility as an adjunct to morphology to differentiate between the 2. Expression of cell-cycle–associated proteins does not influence survival in SCC.