The underlying molecular abnormalities associated with head and neck squamous cell carcinoma in young adults (< 40 years) are unknown. We analyzed DNA extracted from paired microdissected samples of normal squamous epithelia and invasive oral squamous cell carcinomas from 36 young adults at microsatellite loci commonly found in older patients and correlated the results with clinicopathologic parameters and outcome. Our results showed that 30 of the 36 (83%) tumors manifest loss of heterozygosity (LOH) in at least one marker. Microsatellite instability was manifested in only six tumors (< 17%). The highest incidences of alterations were noted at markers D9S168 (9p23-22), TP53 (17p13), and D17S799 (17p11) on the short arms of chromosomes 9 and 17. In general, the incidences of LOH at 3, 9 and 17p regions in young adults were similar to those found in older patients. No correlation between LOH at chromosomes 3, 9, and 17p and clinicopathologic parameters was found. Our study indicates that chromosomal regions with frequent genetic alterations involved in young adult squamous tumorigenesis are similar to those reported in older patients. Further studies of other chromosomes in this population are underway to define the novel molecular features of these tumors.