Previous studies have investigated the associations between TP53 mutations and codon 72 polymorphisms and prognosis in chronic lymphocytic leukemia (CLL). However, the joint effect of TP53 mutations and TP53 codon 72 polymorphisms on CLL prognosis remains uncertain. We used direct sequencing to detect TP53 mutations and codon 72 genotype in 207 patients with CLL. The Pro/Pro genotype was associated with an increased incidence of TP53 mutations and deletion, but had no apparent effect on biological tumor behavior or clinical response. Compared to patients with wild-type p53, patients with TP53 mutations and the Pro72 allele (Arg/Pro + Pro/Pro genotypes) were associated with unmutated immunoglobulin heavy-chain variable region status and chemorefractoriness. Overall survival (OS) in the entire patient group was differed significantly between patients with TP53 mutations and either the Pro72 allele or Arg/Arg homozygotes (P = 0.014). Notably, patients with TP53 mutation and the Pro72 allele experienced a 23.7-fold increase in hazard ratio (95% CI 3.38-165.9; P = 0.001) for OS compared with patients with wild-type p53 and those with the Arg/Arg genotype. The TP53 Pro72 allele potentially increases the prognostic significance of TP53 mutations in CLL.