Polymorphisms of the TP53 gene have been studied extensively, and polymorphisms of codon 72 and intron 6 may be the ones most related to the risk of cancer. However, the relationship of these polymorphisms with a worse prognosis in chronic lymphocytic leukemia is unclear. We analyzed these polymorphisms, using real-time polymerase chain reaction and, in many cases, Sanger sequencing, in 558 patients diagnosed with chronic lymphocytic leukemia. The Pro/Pro genotype was significantly associated with Binet stage B and C chronic lymphocytic leukemia, a higher frequency of Richter transformation, and a shorter time to first treatment for their disease from the time of diagnosis. In contrast, the Arg/Pro genotype was associated with a lower risk of secondary neoplasms. Analyses of overall survival demonstrated that patients with the Arg/Pro genotype lived significantly longer than those with the other genotypes (p = 0.028). In particular, the Pro/Pro homozygous genotype at TP53 codon 72 was identified as an independent variable associated with a 1.7-fold increased risk of death (95% CI: 1.062-2.810; p = 0.028) in comparison with the Arg/Pro heterozygous genotype. These results suggest that the Pro/Pro genotype of TP53 codon 72 has a potential role in the progression and higher mortality of chronic lymphocytic leukemia patients. Conversely, the Arg/Pro genotype was associated with a lower incidence of secondary malignancies and higher overall survival.