For a better understanding of genetic alterations in head and neck squamous cell carcinoma (HNSCC), we applied comparative genomic hybridization (CGH) in the analysis of 75 HNSCCs, comprised of 18 pharyngeal squamous cell carcinomas (PSCCs), 23 laryngeal squamous cell carcinomas (LSCCs), and 34 oral squamous cell carcinomas (OSCCs). The three subgroups of HNSCC showed significant differences in genetic alteration patterns. Overall, PSCC and LSCC had more copy number aberrations (CNAs) per tumor than did OSCC. Apparent differing patterns of high-level amplification were also observed. The smallest recurrent chromosomal regions of high-level amplification (Ն15% of cases) were 7q22, 8q24.1, and 11q12-13 in PSCC and 3q26.1-29 in OSCC. According to single frequency and combined frequencies of CNAs, we concluded that the most important chromosomal events for progression of head and neck cancer were ϩ3q, ϩ5p, ϩ8q, and Ϫ3p for all subgroups of HNSCC; additionally, ϩ7q, ϩ17q, Ϫ9p, and Ϫ13q for PSCC; ϩ7p, ϩ9q, ϩ11q12-13, ϩ14q, and ϩ17q for LSCC; and ϩ1p and ϩ11q12-13 for OSCC. To identify further important genetic alterations and the relationships among the alterations, we constructed oncogenetic tree models for tumor progression of HNSCC from CGH data using branching and distance-based tree models. The tree models predicted that: (1) ϩ3q21-29 was the most important early chromosomal event, and Ϫ3p, which occurred after ϩ3q21-29, was also an important chromosomal event for all subsites of HNSCC; (2) ϩ8q is the second most important early chromosomal event; (3) there may be at least three subgroups of HNSCC: one characterized by Ϫ3p, Ϫ9p, ϩ7p, and Ϫ13q; another by ϩ5p, ϩ9qter, and ϩ17p; and the other by ϩ8q and ϩ18p. These results suggest that different chromosomal aberrations may play a role in the initiation and/or progression of different subgroups of HNSCC.