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The authors conducted a double-blind, randomized, placebo-controlled trial to ascertain whether the use of fluconazole prophylaxis in 125 high-risk, critically ill patients would decrease the incidence of severe candida infection. Secondary objectives included assessing the impact of prophylaxis on mortality and length of hospital stay. Participants were randomly assigned to receive an 800-mg loading dose followed by 400 mg of fluconazole or placebo once daily for the length of their stay in the intensive care unit (ICU). Patients were monitored weekly by the study investigators via physical, hematologic, and microbiologic examinations. Twenty-five patients developed either clinically significant candida infection or severe inflammatory response syndrome (SIRS) within 7 days of discharge from the ICU. However, no significant difference in the incidence of candida infection or SIRS was observed between study groups. Mortality and length of stay were not significantly different between the two groups. Large-scale studies are needed before fluconazole prophylaxis can be recommended in this group of patients.