Acanthamoeba infection is a rare, difficult-to-treat, and often fatal, opportunistic parasitic infection in immunocompromised hosts, such as patients infected with HIV. We describe an aggressive nasal and sinus infection by Acanthamoeba spp. in a person with AIDS. The resolution of this Acanthamoeba infection was secondary to a multidisciplinary treatment approach involving a combination of surgery as well as high-dose amphotericin B plus 5-fluorocytosine. In the era of the HIV/AIDS pandemic, the present report underscores the need for early identification and prompt aggressive treatment to ensure successful management of this rare but potentially fatal opportunistic infection.