The in vitro interaction of antifungals with immunosuppressive drugs was evaluated against zygomycetes. The combination of amphotericin B with cyclosporine, rapamycin, or tacrolimus was synergistic for 90%, 70%, and 30% of the isolates, respectively. For posaconazole, itraconazole, and ravuconazole, synergy was more frequently observed with cyclosporine than with rapamycin or tacrolimus and antagonistic interactions were rarely noted. In summary, calcineurin inhibitors and rapamycin can be synergistic in vitro with amphotericin B and azoles against zygomycetes.