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In general, mortality rates associated with systemic fungal infections have not improved much in more than a decade, although the number of antifungal agents available for the treatment of serious fungal infections has increased in the past few years. A possible approach to decreasing mortality rates associated with fungal infections may be to treat patients with combinations of different classes of antifungals. Recently, in vitro and animal studies evaluating different combinations of antifungal agents have demonstrated important synergistic and/or additive activity against many genera of fungi. However, prudence is required, because some antifungal combinations have demonstrated antagonistic activity. Well-controlled clinical trials are still necessary to define the most efficacious antifungal combination. In addition, these clinical trials should evaluate the adverse event profile of the combination regimens, as well as their pharmacoeconomic impact.