Chronic lymphocytic leukemia (CLL) patients with deletion of chromosome 17p, where the p53 gene is located, often develop more aggressive disease with poor clinical outcomes. To investigate the underlying mechanisms for the highly malignant phenotype of 17p- CLL and to facilitate in vivo evaluation of potential drugs against CLL with p53 deletion, we have generated a mouse model with TCL1-Tg:p53(-/-) genotype. These mice develop B-cell leukemia at an early age with an early appearance of CD5+ / IgM+ B cells in the peritoneal cavity and spleen, and exhibit an aggressive path of disease development and drug resistance phenotype similar to human CLL with 17p deletion. The TCL1-Tg:p53(-/-) leukemia cells exhibit higher survival capacity and are more drug resistant than the leukemia cells from TCL1-Tg:p53wt mice. Analysis of microRNA expression reveals that p53 deletion resulted in a decrease of miR-15a and miR-16-1, leading to an elevated expression of Mcl-1. Primary leukemia cells from CLL patients with 17p deletion also show a decrease in miR-15a/miR-16-1 and an increase in Mcl-1. Our study suggests that the p53/miR15a/16-1/Mcl-1 axis may be an important pathway that regulates Mcl-1 expression and contributes to drug resistance and aggressive phenotype in CLL cells with loss of p53.