Patients having chronic lymphocytic leukemia (CLL) are at increased risk for infectious morbidity and mortality. The predisposition to infections in CLL patients has many components, including both immunodeficiency related to the leukemia itself (humoral and cellular immune dysfunction) and the results of cumulative immunosuppression related to CLL treatment. The risk of infectious complications increases with the duration of CLL, reflecting the natural history of the disease and the cumulative immunosuppression related to its treatment. Hence, in early, untreated CLL, the infectious risk is mainly related to hypogammaglobulinemia, and infections by encapsulated bacteria are common. However, in patients having advanced CLL, particularly those who receive the newer purine analogues, neutropenia and defects in cell-mediated immunity appear to be the major predisposing factors. An expanded spectrum of pathogens, including opportunistic fungi, Pneumocystis carinii, Listeria monocytogenes, mycobacteria, and herpesviruses, are seen in that setting. The changing spectrum of infections in this latter group of patients mandates a newer approach to prophylaxis and therapy.