The study was designed to identify a subset of heart transplant (HT) recipients who could benefit from the administration of targeted antifungal prophylaxis and to evaluate the efficacy of oral itraconazole as the preventive drug. We have analyzed the risk factors for invasive aspergillosis (IA) in our entire population of HT recipients (1988-2002) and also the role of oral itraconazole prophylaxis that was provided to all patients since 1995 [400 mg q.d. of itraconazole oral (PO) for 3-6 months]. There were 24 cases of IA. Our main results indicate that the independent risk factors for IA after heart transplantation are: re-operation (RR 5.8; 95% CI 1.8-18, p=0.002), cytomegalovirus (CMV) disease (RR 5.2; 95% CI 2-13.9, p=0.001), post-transplant hemodialysis (RR 4.9; 95% CI 1.2-18, p=0.02), and the existence of an episode of IA in the HT program 2 months before or after the transplantation date (RR 4.6; 95% CI 1.5-14.4, p=0.007). Itraconazole prophylaxis showed an independent protective value against developing IA (RR 0.2; 95% CI 0.07-0.9, p=0.03) and also determined a significantly prolonged 1-year survival (RR 0.5; 95% CI 0.3-0.8, p=0.01). We believe that antifungal prophylaxis in heart transplant patients should be offered at least to patients with one or more of these predisposing conditions.