Mycobacterium marinum grows at an optimal temperature of 33 degrees C, far lower than that for M. tuberculosis. Consequently, M. marinum infection of mammals is restricted largely to the cooler surfaces of the body, such as the extremities, but it causes a systemic infection in a large number of poikilothermic animals. Here, we describe a laboratory animal model for M. marinum disease in the leopard frog (Rana pipiens), a natural host species. M. marinum causes a chronic granulomatous, nonlethal disease in immunocompetent frogs. Immunosuppression of the frogs with hydrocortisone results in an acute, fulminant, lethal disease. This animal model, in which a spectrum of tuberculosis-like disease can be produced, will be useful for the dissection of the genetic basis of mycobacterial pathogenesis.