The histological transformation from a follicular lymphoma (FL) to a diffuse large B-cell lymphoma (DLBL) occurs in 22% to 30% of all cases of FL. The aim of this study was to identify specific chromosomal gains/losses associated with transformation of FL to DLBL, in addition to the well-known mechanisms like p53 mutation and protein expression and c-myc translocation and up-regulation. This is the first study to meet 2 important conditions for such a comparison. First, we demonstrate that the FL and the DLBL were clonally related, based on identical immunoglobulin gene rearrangements in 5 of the 6 cases. Second, we used laser microdissection microscopy to isolate only the neoplastic cells from the initial FL samples. The results indicate that no single chromosomal abnormality seems to be responsible for the transformation of FL to DLBL. P53 protein overexpression was found in 4 and c-myc translocation in 3 of the 6 transformed DLBLs, but not in the initial FL samples. Additional chromosomal abnormalities were detected by comparative genomic hybridization in all 6 cases when the DLBL was compared with the FL. In the 5 cases with transformation of grade 1 or 2 FL to DLBL, gains at chromosomes 7 (5 of 5 cases), 10p1 (3 of 5 cases), 12 (3 of 5 cases), and 20p13 (2 of 5 cases) and loss at 9q (4 of 5 cases) were the most frequently found abnormalities. A gain on chromosome 7p, in combination with a loss on 9q, was found in 4 of the 5 DLBL that transformed from FL grade 1 or 2.