To clarify the mechanism of tumorigenesis in papillary thyroid carcinoma (PTC) and ascertain whether genomic changes correlate with histologic features, we conducted a comprehensive molecular evaluation of PTC using comparative genomic hybridization (CGH) and microsatellite instability (MSI) analysis in a set of 17 histologically well-characterized PTC specimens. To our knowledge, this is the first study that evaluates chromosomal and nucleotide instability in the same PTC tumor specimens. Four of 15 samples (27%) had aberrations detected by CGH. All four had a partial or complete gain of chromosome 20, and 3 of 4 had a partial or complete loss of chromosome 13. No MSI was detected in any of the PTC samples (n=16), and all samples examined by immunohistochemistry (n=9) expressed the DNA repair enzymes hmlh1 and hmsh2. All PTC samples with abnormal CGH had vascular invasion or invasion of the thyroid capsule, and there was a significant correlation between the presence of chromosomal aberrations and capsular/vascular invasion (P=0.026). We conclude that although chromosomal and microsatellite instability are uncommon in PTC, tumors with chromosomal aberrations are more likely to be associated with invasion.