The genus Acanthamoeba includes species of free-living soil and water ameba that have been implicated in a small number of human diseases. Acanthamoeba species have been identified as the etiologic agents in 2 well-defined clinical entities, amebic keratitis and granulomatous amebic encephalitis (GAE). Less commonly, Acanthamoeba species have been identified as the cause of disseminated disease in debilitated and immunocompromised patients. Cutaneous acanthamebiasis, often a reflection of disseminated disease, is an increasingly recognized infection since the emergence of acquired immunodeficiency syndrome (AIDS) and the use of immunosuppressive drugs. The disease portends a poor prognosis and is uniformly fatal if the infection involves the central nervous system (CNS). We describe a patient with advanced AIDS who presented with disseminated cutaneous lesions, headache, and photophobia, and in whom a diagnosis of cutaneous acanthamebiasis was made based on the results of a skin biopsy. A multidrug therapeutic regimen was begun that included sulfadiazine; the patient responded favorably to treatment. This paper also reviews 36 previously reported cases of cutaneous acanthamebiasis with delineation of clinical, diagnostic, histologic, and prognostic features, as well as discusses treatment options.