Mantle cell lymphoma (MCL) is genetically characterized by 11q13 translocations leading to the overexpression of CCND1, and additional secondary genomic alterations that may be important in the progression of this disease. We have analyzed 22 MCL cases and 10 MCL cell lines using multicolor fluorescence in situ hybridization (M-FISH), FISH, and comparative genomic hybridization (CGH). The 19 cases with abnormal karyotype showed the t(11;14)(q13;q32) translocation and, additionally, 89% of cases showed both numerical (n = 58) and structural (n = 77) aberrations. All but one MCL cell line showed t(11;14) and structural and numerical alterations in highly complex karyotypes. Besides 11 and 14, the most commonly rearranged chromosomes were 1, 8, and 10 in the tumors and 1, 8, and 9 in the cell lines. No recurrent translocations other than the t(11;14) were identified. However, we identified 17 recurrent breakpoints, the most frequent being 1p22 and 8p11, each observed in four cases and two cell lines. Interestingly, five tumors and four cell lines displayed a complex t(11;14), cryptic in one case and two cell lines, preferentially involving chromosome 8. In typical MCL, ATM gene deletions were significantly associated with a high number of structural and numerical alterations. In conclusion, MCL does not have recurrent translocations other than t(11;14), but shows recurrent chromosomal breakpoints. Furthermore, most MCL harbor complex karyotypes with a high number of both structural and numerical alterations affecting several common breakpoints, leading to various balanced and unbalanced translocations. © 2008 Wiley-Liss, Inc.