Using criteria designed for invasive aspergillosis (IA) in patients with cancer, we aimed to determine the impact of IA in patients without malignancy in a medical intensive care unit (ICU). In this retrospective study, 127 patients out of 1,850 admissions (6.9%) hospitalized between 2000 and 2003 had microbiological or histopathologic evidence of Aspergillus during their ICU stay. There were 89 cases (70%) without hematologic malignancy. These patients were classified as proven IA (n = 30), probable IA (n = 37), possible IA (n = 2), or colonization (n = 20). In these patients, mean SAPS II score was 52 with a predicted mortality of 48%. The observed mortality was 80% (n = 71). Mortality of the proven and the probable IA was 97 and 87%, respectively. Postmortem examination was done in 46 out of 71 patients, and 27 autopsies (59%) showed hyphael invasion with Aspergillus. Aspergillus infections occurred in five critically ill patients with proven IA who did not have any predisposing factors according to the currently available definitions. Three of these patients had Child C liver cirrhosis. IA is an emerging and devastating infectious disease in patients in the ICU without malignancy. In those patients, host criteria for probable fungal infections should probably be adapted.