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Complex karyotypes are associated with a poor prognosis in chronic lymphocytic leukemia (CLL). Using mFISH, iFISHand T/C FISH we thoroughly characterized 59 CLL patients regarding parameters known to be involved in chromosomal instability: status of the genes ATMand TP53and telomere length (10 patients with a normal karyotype, 10 patients with an isolated deletion 11q, 19 patients with a complex karyotype without a deletion 11q and 20 patients with a complex karyotype including a deletion 11q). Among the patients with a complex karyotype, 29 of 39 (74%) showed a karyotypic evolution or a composite karyotype expressing great karyotypic heterogeneity and high chromosomal instability. Deletion of TP53and ATM,two master regulators of DNA repair, was mutually exclusive in all but one patient. Interestingly, a deletion in 11q, either isolated or in the complex context of a complex karyotype, was associated with a significantly diminished risk (p<0.05) of carrying a mutation in TP53.In patients with loss or mutation of TP53chromosomal breakage occurred more frequently (p<0.01) in (near-) heterochromatic regions leading to dicentric chromosomes and whole arm translocations. Telomeres of aberrant cells were significantly shorter than those of cells with a normal karyotype from the same patient. Also, median telomere length in patients with complex karyotypes was significantly shorter than of healthy controls (p<0.05) and shorter than telomere length of all other cytogenetic cohorts. Furthermore, the median telomere length of patients carrying a TP53mutation was significantly shorter than of patients without mutation (p<0.05). We conclude that telomere shortening in combination with loss of TP53induces increased chromosomal instability with preferential involvement of (near-) heterochromatic regions.