The natural history of hairy cell leukemia (HCL) includes frequent and potentially life-threatening infections. Prior to the development of effective therapy, the incidence in patients followed for several years was as high as 60%, with infection as a prime cause of death in patients. Studies of the immune system of patients with HCL identified several potential reasons, including profound neutropenia and monocytopenia. In addition, treatment including chemotherapy and splenectomy further compromised the immune system. The success of new therapies has changed the frequency and severity of infections in patients with HCL. During the initial phase of treatment, however, infection risk remains high, with incidence ranging from 30 to 50%. Attempts to ameliorate the risk with growth factors in conjunction with treatment have not been successful, but lower doses of drugs and/or combination therapy have been tried with reported success. In the majority of patients, successful therapy results in normalization of the neutrophil count and marked reduction in the severity and frequency of infections. Interestingly, after purine nucleoside treatment, there is profound depression of CD4+ cells without development of the opportunistic infections seen with patients with human immunodeficiency virus (HIV). Studies to reduce morbidity and mortality should focus on initial induction regimens, as well as confirming the long-term benefit of treatment on risk of infection.