Fibrolamellar hepatocellular carcinoma (FLC) is a rare entity of hepatocellular carcinoma (HCC) not yet analyzed cytogenetically. By using comparative genomic hybridization (CGH), we looked for chromosome changes in 2 primary FLCs and a recurrent FLC with and without metastases. CGH revealed an amplification of 1q in 1 primary FLC. The other primary FLC and a metastasis revealed no changes. The recurrent FLC showed 18 aberrations, including 1q+, 2p+, 3p+, 3q+, 4p+, 4q+, 5p+, 5q+, 6q+, 8p+, 8q+, 9q+, 12p+, 12q+, 18p+, 18q+, Xp+, and Xq+. In 2 metastases, 9 and 10 aberrations were seen, including 1q+, 3p-, 3q-, 4q+, 5p+, 5q+, 8q+, 10p+, 10q+, Xp+, and Xq+. In 9 cases of other entities of HCC, a mean of 10.2 aberrations per case were detectable affecting 1q (7 cases), 4q (5), 5q (4), 6q (5), 8p (5), 8q (5), 9p (4), 9q (5), 16q (4), 17p (5), and 17q (4). Chromosomes 2p, 2q, 3p, 3q, 4p, 5p, 6p, 7p, 7q, 10q, 11p, 11q, 12p, 12q, 13q, 14q, 16p, 18p, 18q, 20p, 20q, and 21q were altered in up to 3 samples. Our findings indicate striking differences in the number of chromosomal imbalances in primary FLC and recurrent FLC, whereas imbalances seen in the recurrent FLC and the other entities of HCC were similar in number and chromosomes involved. It may be speculated that these aberrations represent secondary events based on a genetic instability and do not mirror the primary alterations in these carcinomas.