The poor prognosis of chronic lymphocytic leukemia (CLL) patients with del (17p) is well established. We analyzed whether mutation of TP53 on the remaining allele adds to the poor prognosis or whether even TP53 mutation alone may be an adverse prognostic factor. We analyzed TP53 mutations in 193 CLL patients by denaturing high performance liquid chromatography in combination with direct DNA sequencing and a TP53 resequencing research microarray. Mutations were correlated to chromosomal aberrations defined by interphase fluorescent in situ hybridization and chromosome banding analyses and to the clinical course of patients. TP53 mutations were detected in 13.5% (26 of 193) of samples, whereas the incidence of del (17p) was 9.3% (18 of 193). TP53 mutations were significantly associated with del (17p) (concordance 94%, P<0.001) and complex cytogenetic abnormalities (concordance 50%, P<0.001). Among 147 patients whose clinical data were available, patients with TP53 abnormalities (n=20) had a significantly decreased time to treatment compared to patients without TP53 aberration (P<0.001). Median time to treatment was short in patients with isolated TP53 mutation (n=6, 2.0 months) and in those with del (17p) (n=14, 21.3 months) as compared to patients without TP53 aberration (n=127, 64.9 months, P<0.001). In multivariate Cox regression analysis, VH status, TP53 mutations and also isolated TP53 mutations independently predicted rapid disease progression.