Patients with mantle cell lymphoma (MCL) may present with either nodal or leukemic disease. The molecular determinants underlying this different biologic behavior are not known. This study compared the pattern of genetic abnormalities in patients with nodal and leukemic phases of MCL using comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) for specific gene loci. Although both leukemic and nodal MCL showed similar genomic patterns of losses (involving 6q, 11q22-q23, 13q14, and 17p13) and gains (affecting 3q and 8q), genomic loss of chromosome 8p occurred more frequently in patients with leukemic disease (79% versus 11%, P <.001). Subsequent CGH analysis confirmed the genomic loss of 8p21-p23 in 6 of 8 MCL cell lines. Interestingly, MYC gene amplification was restricted to cases with 8p deletion. These data indicate the presence of a novel tumor suppressor gene locus on 8p, whose deletion may be associated with leukemic dissemination and poor prognosis in patients with MCL.