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Objectives: Free-living amoebas are exceedingly rare causes of cutaneous infections and present unique diagnostic and therapeutic challenges. We describe a case of disseminated acanthamoebiasis with cutaneous manifestations and summarize additional diagnostic, prognostic, and therapeutic highlights. Methods: A 58-year-old man with relapsed chronic lymphocytic leukemia had several weeks of progressive, painful ulcerations on the forehead, arms, abdomen, and thighs. A biopsy was performed for histopathologic evaluation. Results: The biopsy specimen showed inflammatory infiltrate with abscess formation involving the epidermis, dermis, and subcutis. Scattered cells showed nuclei with a prominent central karyosome, dispersed chromatin, and either abundant foamy basophilic cytoplasm or two well-demarcated cytoplasmic walls. Acanthamoeba species was confirmed by polymerase chain reaction from the formalin-fixed, paraffin-embedded tissue. Conclusions: Cutaneous lesions from acanthamoebiasis are exceptionally rare but should be included in the differential diagnosis of necrotic cutaneous lesions in immunocompromised patients. Although infrequently encountered, pathologists need to be aware of the morphologic features of free-living amoebas. Immunohistochemical and molecular studies can confirm the diagnosis. Multiagent treatment regimens, when initiated empirically, have been more successful than single-agent regimens, but infections involving the central nervous system are almost universally fatal.