Zygomycosis refers to any fungal infection originating from the class Zygomycetes and the order Mucorales. In immunocompromised patients, these fungi produce a relatively rapid, violently destructive, and highly fatal infection. Treatment approaches include both aggressive antifungal pharmacotherapy and surgical intervention. Unfortunately, even with optimal therapy, morbidity and mortality rates remain relatively high. As failure rates are elevated with commercial antifungals, new treatment options are needed. Posaconazole is an orally available, extended-spectrum triazole antifungal being investigated in phase III clinical trials for the treatment and prevention of invasive fungal infections, including zygomycosis. We report the case of a 26-year-old Vietnamese man with a medical history of acute lymphocytic leukemia who had undergone consolidation chemotherapy and had neutropenic fever when he came to the emergency department. The patient was admitted to the hospital and treated with broad-spectrum antibiotics and caspofungin. Two weeks into his admission, however, abscesses in the pelvis, prostate, and musculature surrounding the hip were detected radiographically; these abscesses eventually cultured for Mucor sp. Disseminated zygomycosis was diagnosed. Caspofungin was immediately discontinued, and high-dose liposomal amphotericin B 10 mg/kg/day was begun. Over the next month, infection spread to the right lung, left kidney, middle thoracic spine, and epidural space. As a result, oral posaconazole 200 mg 4 times/day was added to the liposomal amphotericin B. Significant clinical, hematologic, mycologic, and radiologic improvements were demonstrated as early as 10 days after start of posaconazole therapy and continued through 41 days of inpatient treatment. Liposomal amphotericin B was discontinued after 3 weeks of posaconazole, and the patient was discharged on hospital day 92 receiving oral posaconazole, with no major adverse events reported. Five months after discharge, the patient had no evidence of fungal disease recurrence or progression. Posaconazole appears to be a well-tolerated and effective salvage treatment for zygomycosis, including disseminated disease.