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The treatment of zygomycosis has two cornerstones, namely, surgery and antifungal drugs. In many patients, both need to be applied to achieve treatment success; without treatment, the mortality rate of zygomycosis approaches 100%. Because treatment options are limited, no well-designed randomized clinical trial has been conducted and data are predominantly derived from compassionate-use programmes or case reports. Amphotericin B (AmB) lipid complex (ABLC) was clinically evaluated for efficacy against zygomycosis in a single series and resulted in cure or improvement in 52% and in the stabilizing of disease in 20% of patients. Liposomal AmB (L-AmB) is frequently used, but no large series have yet been published. Posaconazole has demonstrated in vitro and in vivo activity against Zygomycetes. Two series demonstrated salvage treatment response rates of 60% and 79%, respectively. Antifungal combinations have not been evaluated thoroughly enough to warrant recommendations outside of clinical trials. Survival is usually associated with surgical debridement and improvement in underlying diseases. Currently, surgical debridement should be performed. Antifungal treatment should consist of either ABLC > or =5 mg/kg once per day or L-AmB > or =3 mg/kg once per day. When toxicity occurs or stable fungal disease is achieved, treatment can be switched to oral posaconazole 200 mg four times per day. If impaired kidney function is overt or expected on the grounds of, for example, uncontrolled diabetes, primary treatment of zygomycosis with posaconazole is an option.