BACKGROUND AND OBJECTIVES: Sezary's syndrome is a peripheral T-cell neoplasm characterized by a pruritic exfoliative or infiltrated erythroderma, lymphadenopathies, and atypical T lymphocytes in the peripheral blood. Cytogenetic studies are scarce. This study was designed to increase cytogenetic information on this disorder. DESIGN AND METHODS: Peripheral blood samples were collected from 21 patients with Sezary's syndrome (10 men, 11 women, mean age 64 years) and analyzed by conventional cytogenetics (72-hr cultures with phytohemagglutinin). For a better characterization of multiple chromosomal rearrangements, cross-species color banding (RxFISH) was used in four cases. RESULTS: Fifteen (71.4%) of the 21 cases showed cytogenetic aberrations, with the karyotype being complex in 14. Among the 15 patients with an abnormal karyotype, 8 presented a diploid/near-diploid karyotype and 7 a near-tetraploid karyotype. The chromosomes most frequently involved were 1, 6, 8, 9, 10, 11, and 17. The most common structural rearrangements affected 1q, 2q, 6q23-27, and 8q22. Monosomies of chromosomes 9 and 10 and trisomies of chromosome 18 were recurrently observed. A statistical trend between abnormal and complex karyotypes, the presence of monosomy 10, the number of Sezary cells, and a decreased overall survival was observed. RxFISH technology allowed the description of 27 previously undetected chromosomal abnormalities. INTERPRETATION AND CONCLUSIONS: Abnormal karyotypes, particularly complex karyotypes, were frequently detected in patients with Sezary's syndrome. Monosomy 10 was the most frequent recurrent cytogenetic marker (73% in abnormal cases). There was a high diversity of chromosomal breakpoints. RxFISH is a useful novel technology for redefining complex karyotypes.