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Background. Antifungal prophylaxis after heart transplantation is usually targeted to high-risk recipients, but the duration is normally fixed and empirical. Our purpose was to assess the efficacy of a personalized prophylactic approach based on the duration of the risk factors. Methods. In a prospective cohort, from 2003 to 2010, prophylaxis was only administered to patients with risk factors (13 of 133) and duration was personalized, starting with the risk factor and continued a median of 20 days after its resolution. Results. Antifungal prophylaxis was prescribed only in 9.8% of the recipients and was effective in all but one patient who should have received a higher dose of caspofungin due to his obesity. Despite suffering an outbreak of invasive aspergillosis (IA) in the intensive care unit due to extremely high concentration of spores in the air (three cases with no personal risk factors), there was a reduction in the incidence of IA (8.6% vs. 2.2%; P=0.01) and Aspergillus-related mortality (5.75% vs. 1.5%; P=0.06). Conclusions. Targeted prophylaxis for IA in heart recipients provided only to patients with risk factors and maintained for a median of 20 days after their disappearance is effective and safe. A high environmental load of Aspergillus spores in the intensive care unit would also indicate the need for antifungal prophylaxis in all exposed patients.