OBJECTIVES: Neutropenic patients treated with chemotherapy for hematological malignancies and recipients of allogeneic hematopoietic stem cells transplantation (HSCT) are at high risk of acquiring invasive fungal infections (IFIs). Prognoses for IFIs are poor in terms of mortality and morbidity. An important factor in improving outcome is early treatment with antifungal agents. Early treatment, however, is complicated by a number of factors, including poor diagnostic measures. As a consequence, antifungal prophylaxis may be an effective strategy. Use of antifungal prophylaxis remains a matter of controversy, without a clear consensus on the choice of drug treatment. In this study, we used mixed treatment comparison (MTC) methodologies to compare the effectiveness of different antifungal drugs used in prophylaxis treatments against IFIs in high-risk patients. METHODS: Through systematic and transparent methodologies, MTC techniques allow for the combination of evidences from different sources and as a result may provide information where none exists or where direct comparisons are incomplete. For the estimation of effectiveness, we collected evidence on proven or probable IFIs from 13 different randomized clinical trials (RCTs). Comparisons of interest included placebo, fluconazole, itraconazole, voriconazole, and micafungin. The MTC analyses were carried out through the application of Bayesian hierarchical models. RESULTS: Significant evidence was found on the superiority of all study drugs versus placebo for preventing IFIs. Furthermore, MTC analyses indicated that the probability of acquiring an IFI after voriconzole prophylaxis is significantly lower than after fluconazole prophylaxis (dOR=0,17 95%CI = [0.03,0.94]). Comparisons between all other antifungals yielded no significant differences in incidence of IFIs. CONCLUSIONS: After the application of MTC methodologies on RCT evidence, the authors found evidence suggesting that prophylaxis with antifungals is superior to placebo and prophylaxis with voriconazole is superior to fluconazole regarding reduction in incidence of IFIs.