We recently identified a heterozygous mutation in the beta1 integrin subunit of a squamous cell carcinoma (SCC) that maps to the I-like domain and activates ligand binding. To investigate the frequency of such mutations we screened 124 human oral SCCs. We identified six single nucleotide changes, all of which were also present in normal tissue, suggestive of polymorphisms. Two were in non-coding intronic sequences. Three were silent changes in exons. One caused a change in amino acid (A239V) that is unlikely to disturb integrin structure. We conclude that mutations in the beta1 I-like domain are uncommon in SCCs. However, population based studies of the polymorphisms we found may reveal an association with SCC development or prognosis.