The natural history of American cutaneous leishmaniasis was studied in Guatemala by analyzing the characteristics of 355 untreated leishmanial lesions, observing the evolution of 57 lesions on persons who received a placebo in treatment trials, and analyzing data from a population-based survey concerning the duration of 82 untreated lesions. Of 25 lesions caused by Leishmania mexicana that were followed prospectively, 22 (88%) completely reepithelialized by a median lesion age of 14 weeks, and 17 (68%) were classified as cured (no residual wound inflammation or reactivation during at least 6 months of follow-up). In contrast, 7 (22%) of 32 lesions caused by Leishmania braziliensis reepithelialized by a median lesion age of 13 weeks, and only 2 (6%) cured. These data demonstrate that the species of Leishmania is the primary determinant of the clinical course and outcome of untreated lesions and underscore the need for field-applicable diagnostic techniques that provide rapid species identification.