Gene amplifications and deletions are frequent in head and neck squamous cell carcinomas (SCC) but the association of these alterations with gene expression is mostly unknown. Here, we characterized genome-wide copy number and gene expression changes on microarrays for 18 oral tongue SCC (OTSCC) cell lines. We identified a number of altered regions including nine high-level amplifications such as 6q12-q14 (CD109,MYO6), 9p24 (JAK2,CD274,SLC1A1,RLN1), 11p12-p13 (TRAF6,COMMD9,TRIM44,FJX1,CD44,PDHX,APIP), 11q13 (FADD,PPFIA1,CTTN), and 14q24 (ABCD4,HBLD1,LTBP2,ZNF410,COQ6,ACYP1,JDP2) where 9% to 64% of genes showed overexpression. Across the whole genome, 26% of the amplified genes had associated overexpression in OTSCC. Furthermore, our data implicated that OTSCC cell lines harbored similar genomic alterations as laryngeal SCC cell lines we have previously analyzed, suggesting that despite differences in clinicopathological features there are no marked differences in molecular genetic alterations of these two HNSCC sites. To identify genes whose expression was associated with copy number increase in head and neck SCC, a statistical analysis for oral tongue and laryngeal SCC cell line data were performed. We pinpointed 1,192 genes that had a statistically significant association between copy number and gene expression. These results suggest that genomic alterations with associated gene expression changes play an important role in the malignant behavior of head and neck SCC. The identified genes provide a basis for further functional validation and may lead to the identification of novel candidates for targeted therapies. This article contains Supplementary Material available athttp://www.interscience.wiley.com/jpages/1045-2257/suppmat.