Experimental evidence points to the role of Zinc fingers and homeoboxes protein 1 and 2 (ZHX1 and ZHX2) in the development and progression of several types of cancer, including hematological malignancies. Here, we determined whether the altered expression of ZHX1 and ZHX2 has clinical implications in patients with CLL. Interestingly, CLL patients with low expression ZHX1 and ZHX2 presented higher WBC counts. Importantly, our data showed that CLL patients with cytogenetic alterations presented reduced transcriptional levels of ZHX1 and ZHX2 in comparison with patients with normal karyotype. Moreover, when stratifying CLL patients according to the karyotype prognosis value, we observed that the expression of ZHX1 and ZHX2 was significantly reduced in CLL patients presenting adverse karyotypes. Finally, we stratified patients according to the number of chromosomal aberrations and observed a negative association between ZHX1 and ZHX2 expression and the accumulation of chromosomal abnormalities in CLL patients. Our data showed that the low expression of ZHX1 and ZHX2 is associated with a worse prognosis in CLL, followed by a greater number of leukemic cells and unfavorable cytogenetics findings in the diagnosis. Further studies will be important to confirm the prognostic value of ZHX1 and ZHX2 in independent CLL cohorts.