These findings demonstrate that: (i) mutations of the cell cycle regulatory genes p16 and p21 and the S100A4 gene are infrequent and might be unnecessary in development and/or progression of oropharyngeal SCCs, (ii) the results were not found to relate to previous results of p53, (iii) loss of p21 and/or p53 might not predict for prognosis in these cancers, (iv) the absence of mutations of the three genes examined in the cases previously found mutated for p53 might suggest that these mutations are complementary to p53 mutations in the development of these cancers, but the lack of these mutations in the cases with no mutations in p53 might suggest that the pathogenesis of these cancers may follow other independent pathways.