T-cell prolymphocytic leukemia (T-PLL) is a rare postthymic T-cell disorder that may show different morphologic variants and a very aggressive clinical behavior. On occasion, patients may present with an indolent clinical course and long survival. The disease is genetically characterized by the presence of complex karyotypes with recurrent alterations involving chromosomes 8, 14, and 11. The possible relationship between genetic alterations and morphologic variants and the clinical course of the disease, however, is not well known. Comparative genomic hybridization (CGH) was used to detect chromosomal imbalances in eight patients diagnosed with T-PLL, including three cases of small-cell variant with an indolent clinical evolution. Abnormal profiles were detected in all cases. The chromosomal regions most often over-represented were 8q (75%), 5p (62%), and 14q (37%), as well as 6p and 21 (both 25%). The chromosomal regions most often underrepresented were 8p and 11q (75%), 13q (37%), and 6q, 7q, 16q, 17p, and 17q (25%). The number of chromosomal imbalances in the three small-cell variants was relatively similar to that of cases with typical morphology. Only gains of 6p and losses of 7q present in three and two cases, respectively, with typical morphology were not detected in any small-cell variant. CGH analysis revealed alterations in 15 chromosomal regions not detected by conventional cytogenetics. These results indicate that T-PLL carry a high number of chromosomal alterations that are not related to the morphologic variants or the clinical behavior of the disease.