Acutely ill patients who are immunocompromised but not neutropenic most commonly are: (1) diabetic; (2) on chronic high-dose steroid therapy; (3) have lupus; or (4) have impaired or absent splenic function. These patients often present in the CCU because of the severity of their infection. Differential diagnosis may be approached by first considering the patient's underlying disease, i.e., SLE. The next step in the diagnostic process is to appreciate the immune defect associated with these disorders. The nature of the immune defect determines which clinical pathogens are related to the immune defect. Pathogens are associated with a sterotyped pattern of organ involvement. The object of the diagnostic analysis is to determine the most likely organism affecting a particular organ system, given the defect in host defenses associated with the patient's underlying illness. In this way, a useful clinical diagnosis can be made rapidly, and appropriate clinical specimens obtained for diagnostic testing. Often empiric therapy must be started pending the results of diagnostic testing. In such situations, empiric therapy ordinarily is directed against the bacterial pathogens most likely to cause disease relevant to the patient's impaired defenses. Specific therapy for unusual or exotic pathogens should not be empiric and should be based on demonstration of a pathogenic role by the microorganism. In the case of miliary tuberculosis or invasive fungal disease, a case may be made for early empiric therapy to cover these organisms if there is sufficient clinical suspicion based on the presenting signs and symptoms as well as the pattern of organ involvement. As with all infections, but particularly in immunocompromised patients, the early initiation of appropriate antimicrobial therapy is essential and often life-saving.