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We analyzed TP53 mutations in 483 chronic lymphocytic leukemia patients at different phases of the disease and found a higher incidence of mutations at the later phases and a distinctive mutation profile in each phase. p53 function evaluated by immunoblotting and flow cytometry after cell irradiation was impaired in 28 of 109 cases. Three phenotypically different dysfunctions were observed: type I, associated with heterozygous missense TP53 mutations (typically present at diagnosis) and partially resistant to radiation-induced killing; types II and III, with a higher incidence of microdeletions, nonsense mutations and bi-allelic TP53 defects (common in progressive and chemoresistant cases) and a complete radioresistance. Furthermore, in 4 of 28 patients, all chemoresistant, we found p53 dysfunctions without TP53 mutations. In chronic lymphocytic leukemia patients, a disease phase-specific variability in the p53 mutation profile and function takes place, and both analyses could be useful to guide treatment choices.