Acanthamoeba organisms are a well-known, although rare, cause of central nervous system infection in immunodeficient hosts, including those with the acquired immunodeficiency syndrome. Extracerebral acanthamebiasis, with the exception of contact lens-associated keratitis, is reported but little emphasized in the literature. We describe two patients with the acquired immunodeficiency syndrome in whom skin lesions were the primary manifestations of Acanthamoeba infection. Central nervous system disease was proved in one patient and suspected, but unproved, in the other. The skin lesions exhibited an intact epidermis with suppurative inflammation of the subcutis, associated with numerous amebic cysts and trophozoites. The amebic cyst walls stained with periodic acid-Schiff and Gomori's methenamine-silver stains, creating confusion with Blastomyces dermatitidis yeast in one instance. Immunofluorescence studies and culture identified the organisms as an Acanthamoeba species. Preliminary studies in one of the cases suggested a previously undescribed Acanthamoeba species as the etiologic agent. Our experience emphasizes that skin lesions may be the presenting sign of disseminated Acanthamoeba infection in patients with the acquired immunodeficiency syndrome.