Acanthamoeba, a free-living ameba of soil and water, produces the rare infections of granulomatous amebic encephalitis and amebic keratitis. We report a 38-year-old white man with the acquired immunodeficiency syndrome (AIDS) who experienced Acanthamoeba infection that presented as multiple skin nodules without associated encephalitis. Histologic examination revealed necrotizing granulomatous inflammation with numerous amebic organisms that were cultured and identified as Acanthamoeba group 2, probably Acanthamoeba castellani by monoclonal antibodies. Results of in vitro susceptibility testing demonstrated resistance to all six tested drugs. A partial clinical response, however, was obtained with multidrug therapy.