B-cell chronic lymphocytic leukemia is associated with immune suppression and an altered T-cell repertoire with expansion of memory cells. Cytomegalovirus (CMV) is a common herpes virus that elicits a strong virus-specific T-cell immune response after infection. We studied the CMV-specific CD4(+) T-cell response in 45 patients and 35 control subjects and demonstrated that it was markedly expanded in the patient group, averaging 11% of the CD4(+) pool compared with 4.7% in controls. The magnitude of the CMV-specific CD4(+) immune response increased with disease stage and was particularly high in patients who received chemotherapy. Within this group, the CMV-specific response comprised over 46% of the CD4(+) T-cell repertoire in some patients. Serial analysis revealed that CMV-specific immunity increased during treatment with chemotherapy and remained stable thereafter. CMV-seropositive patients exhibited a markedly altered CD4(+) T-cell repertoire with increased numbers of CD45R0(+) T cells and a reduction in CD27, CD28, and CCR7 expression. Overall survival was reduced by nearly 4 years in CMV-seropositive patients, although this did not reach statistical significance. CLL patients therefore demonstrate an expansion of the CD4(+) CMV-specific immune response, which is likely to contribute to the immunological and clinical features of this disease.