In this study, we report the occurrence of missense mutations of the transforming growth factor beta (TGF beta) type II receptor gene in two human squamous head and neck carcinoma cell lines. Both mutations are G:C-->C:G transversions, which result in the replacement of a glutamic acid by a glutamine, and of an arginine by a proline residue, respectively. Moreover, both are located at highly conserved sites within the serine-threonine kinase domain. One of the mutants appears to be defective in its autophosphorylation as well as in the transphosphorylation of the TGF beta type 1 receptor protein, whereas the second mutant appears to be constitutively activated. These are the first reported naturally occurring nucleotide substitution mutations in the T beta R-11 gene in human head and neck cancer cells, which may explain their resistance to TGF beta 1-mediated cell cycle arrest.