Mucormycosis is a potentially fatal, rapidly destructive, opportunistic infection often seen in immunocompromsied individuals and patients with diabetes mellitus. We describe two patients with rhino-orbital mucormycosis caused by Rhizopus oryzae who received posaconazole within 7 days of diagnosis and in whom cure was achieved in conjunction with extensive surgical resection of diseased tissue. Posaconazole was well-tolerated. Our experience indicates that this new extended-spectrum azole antifungal agent can be used early in the course of zygomycete infection with good results.