To test whether herpetofauna could be a laboratory model for Mycobacterium ulcerans, 21 anole lizards were inoculated subcutaneously with viable M. ulcerans, 21 with autoclaved organisms, and 14 with an aqueous solution of 0.01% Tween 80. M. ulcerans was recovered in culture from the slowly progressive lesions which developed at the inoculation site in lizerds receiving the viable bacteria. Progressive lesions did not occur in the two control groups. Three patterns of inflammatory response to viable M. ulcerans were observed: 14 lizards developed a diffuse, granulomatous reaction in which acid fast bacilli (AFB) were predominantly intracellular; 1 developed focal, encapsulated granulomas; 5 developed a diffuse, necrotizing granulomatous response in which most AFB were extracellular—similar to the characteristic lesion found in human infections.