The susceptibility of congenitally athymic rats to M. leprae infection has been investigated. Following inoculation of small numbers of M. leprae (5 .times. 103) into the foot pad, the organisms replicated and attained a maximum of 2.6 .times. 108/foot pad at 294 days; there was limited dissemintation to the tail. In similarly inoculated neonatally thymectomized Lewis rats (NTLRs) a ceiling of 2 .times. 107 organisms was reached. When a larger inoculum (107) was given, the number of bacilli in athymic rat food pads peaked at 6.7 .times. 108 and after .apprx. 240 days a plateau of 2-6 .times. 108/foot pad was reached. Dissemination to superficial tissues occurred .apprx. 9 mo. after inoculation, when significant numbers of bacilli were recovered from the foot pads, ears, snout and tail. Following i.v. inoculation of 107 M. leprae into athymic rats, significant numbers of bacilli were recovered from the superficial tissues by 300 days post inoculation. The numbers of organisms reached a plateau of .apprx. 108 by 1 yr. Autopsy of infected animals from 1-2 yr after inoculation revealed no gross abnormalities except for a purulent bronchitis and bronchopneumonia. Although normal grossly, the ears, tail, snout and foot pads showed a varying degree of infiltration by histiocytes. In some this was almost imperceptible, in others there were large accumulations of foamy macrophages reminiscent of lepromatous leprosy. The numbers of mycobacteria present in Fite stains ranged from 2+ (several organisms or clusters of organisms) to 5+ (very numerous). The lymph nodes contained numerous non-caseating granulomata composed of activated macrophages which contained large (4+) or very large (5+) numbers of bacilli. Mycobacteria were present in the cells of the mononuclear-phagocyte series in the liver and spleen of animals killed 12-15 mo. post inoculation, but were absent from these cells in animals killed later. M. leprae were also numerous in the smooth muscle of the scrotum. It is concluded that congenitally athymic rats are highly susceptible to M. leprae infection. Despite their lack of thymic-dependent T cell function, it appears that they possess the defense mechanism(s) capable of limiting the infection.