Blastomycosis has become increasingly recognized as a serious infection in immunocompromised hosts in recent years. Underlying disorders among these patients include conditions that are typically characterized by abnormalities of T-lymphocyte function such as acquired immunodeficiency syndrome, long-term glucocorticosteroid use, hematologic malignancy, solid organ transplantation, and pregnancy, in addition to a variety of other diseases. Clinically, the disease in immunocompromised patients is potentially much more severe and is characterized by disseminated multiple organ involvement including frequent involvement of the central nervous system. Adult respiratory distress syndrome and/or miliary pulmonary involvement, relatively rare complications in the normal population, are also common in immunocompromised patients. Most notably, mortality as a result of blastomycosis in these patients exceeds 30% and usually occurs within several weeks of presentation. Because of the severity of the disease, initial therapy with amphotericin B is advised for most immunocompromised patients with blastomycosis to gain control of the disease. The role of itraconazole as initial therapy is probably limited to patients with focal, uncomplicated disease. Many of these patients, particularly those with conditions associated with ongoing immunosuppression, require chronic suppressive therapy with an azole to prevent relapsing disease.