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The ataxia telangiectasia mutated (ATM) protein is the principal activator of the p53 protein in the response to DNA double-strand breaks. Mutations in the ATMgene have been previously found in B-cell chronic lymphocytic leukemias (B-CLLs) but their clinical significance is unknown. We analyzed 155 CLL tumors and found 12% with ATMmutations and 4% with TP53mutations; 2 tumors contained mutations in both genes. Retrospective analysis on selected samples indicated that the ATMmutations were usually present at diagnosis. Compared with patients with wild-type ATM/TP53genes, patients with ATMmutations had statistically significantly reduced overall and treatment-free survival. Although present in both IGVHmutation subgroups, ATMmutations were associated with unmutated IGVHgenes and they provided independent prognostic information on multivariate analysis. Mutations in the ATMgene resulted in impaired in vitro DNA damage responses. Tumors with ATMmutations only partially correlated with tumors with loss of an ATMallele through an 11q deletion and, interestingly, those 11q-deleted tumors with a second wild-type ATMallele had a preserved DNA damage response. The majority of patients with ATMmutations were refractory to DNA damaging chemotherapeutic drugs and as such might benefit from therapies that bypass the ATM/p53 pathway.