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To our knowledge, an institutional review of systemic histoplasmosis has not been conducted in the United States since the major outbreaks in Indianapolis in 1978-4982. We conducted a retrospective review of all patients with systemic histoplasmosis diagnosed at Mayo Clinic over a 15-year period. The case definitions employed were based on an international consensus statement by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC/IFICG) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG). One hundred eleven patients with systemic histoplasmosis were identified between January 1, 1991, and December 31, 2005. Of these, 78 patients had disseminated histoplasmosis and 55 patients had Histoplasma capsulatum fungemia. The mean age of patients was 55 years, 66% were male, and 98% were white. Fifty-nine percent of patients were immunocompromised. Fever was the most frequently reported symptom (63%), followed by respiratory complaints (43%) and weight loss (37%). The peripheral white blood cell count was <3000 cells/mm3 in 28%, hemoglobin was <10 g/dL in 29%, and platelet count was <150,000 cells/mm3 in 41% of patients. Liver enzymes were elevated (alanine aminotransferase >60 U/L in 39%, aspartate aminotransferase >60 U/L in 27%), alkaline phosphatase was >200 U/L in 55%, and albumin was <3.5 g/dL in 70%. Serologic and histopathologic examinations were each positive in 75% of cases, Histoplasma urine antigen screening was positive in 80%, and H. capsulatum was culture positive in 84%. Forty-seven percent of patients were sequentially treated with an amphotericin B-containing product followed by itraconazole, 31% received itraconazole alone, and 7% received an amphotericin B-containing product only. Another 13% of patients did not receive antifungal treatment, and the remaining 2% did not have treatment data available. Sixty percent of patients required hospitalization, and in hospital mortality was 6% with a median survival time of 61 days. The relapse rate was 9%, with a median relapse-free survival of 857 days. Systemic histoplasmosis should be suspected in patients who have lived in endemic areas with fever, bone marrow suppression, and elevated hepatic enzymes, particularly if they are immunocompromised. Evaluation including a combination of Histoplasma serologic screening, urine antigen assay, and fungal culture will secure the diagnosis in most cases.