Although cutaneous amebiasis (CA) is a rare disease, it is a public health concern worldwide, particularly in developing nations. It gains importance because of its severe clinical course, which can be confused with other disorders. Therefore, knowledge of its clinical features, histopathology, and pathogenesis is essential. We present a retrospective analysis over 50 years of 26 patients with CA who were diagnosed and treated at 2 Mexican institutions. Our main focus was to draw clinical information to identify mechanisms by which amebae reach the skin, occurring in a relatively small percentage of infected individuals. The recorded data included age and sex of the patients, form of presentation, any associated illnesses and/or factors, and methods for diagnosis. Histologic slides were reviewed in all cases; cytologic preparations also were available for 6 cases. Most patients were male (overall male to female ratio, 1.9 to 1). The disease always presented as painful ulcers containing varying amounts of amebae microscopically; the amebae were fairly easy to identify with routine stains, particularly when examination of tissue or smears was prepared from the edges of the ulcer instead of the necrotic centers. Erythrophagocytosis by the trophozoites was found and represented an unequivocal sign of its pathogenicity. We review the 2 mechanisms by which the organisms reach the skin. Most cases resolve with the use of specific antiamebic drugs; however, if left untreated, progression is rapid and unrelenting, sometimes with massive destruction of skin and subcutaneous tissues. Therefore, CA is a particularly virulent form of amebiasis.