Interferon regulatory factor 4 (IRF4) is a member of the interferon regulatory factor family of transcription factors and has been shown to have critical functions at several stages of B-cell development. Genome-wide association study identified a polymorphism in the 3' untranslated region of IRF4 as a chronic lymphocytic leukemia risk locus. In this study, we report a recurrent heterozygous somatic mutation in the DNA-binding domain of IRF4 detected in 7 of 457 chronic lymphocytic leukemia patients (1.5%). Patients with IRF4 mutation have a good prognosis, and 4 of 6 have a trisomy 12. We also found that IRF4 mRNA expression is higher in the patients with the mutation.