We describe what we believe is the first reported case of simultaneous highly invasive cutaneous and laryngopharyngeal zygomycosis in a non-neutropenic, nondiabetic but immunosuppressed patient with prostate cancer. An invasive fungal process was not suspected until late in the patient's hospital course; when it was, a tracheotomy and direct laryngoscopic biopsies were performed. Unresectable invasive zygomycosis with Rhizopus rhizopodiformis was diagnosed. The patient was managed with liposomal amphotericin B initially and later with palliative medical therapy until he died. This case emphasizes the need for a rapid and specific diagnosis with timely introduction of appropriate antifungal management, particularly now that voriconazole is frequently used as empiric prophy-laxis against aspergillosis in high-risk patients.