Genomic instability in simple repeated sequences has been observed in several human cancers. We have analyzed 50 squamous cell carcinomas of the head and neck (SCCHN) and 5 pre-malignant severe dysplastic tissues from Indian patient populations for microsatellite instability in 18 different loci spread over eight different chromosomes. Among the tumors analyzed, 45% exhibited instability at two or more loci, and 15% exhibited instability at 40% of the markers tested. Similar analysis of SCCHN tumors from other populations (British, American and French) showed much less frequency of instability. SCCHN tumors in the present study did not show any instability in the mononucleotide repeat sequences. There is also a clear distinction in the nature of the instability in these tumors in comparison with colorectal tumors. These results suggest that the underlying mechanism generating this type of instability is different from those reported for colorectal tumors.