Intravenous immunization with a cell extract of Mycobacterium leprae produced a primary immune response of considerable magnitude, followed by an equally large response after secondary stimulation, as measured by assay of plaque-forming cells (PFC). Infection with M. leprae or immunization with cell extract by the footpad route produced a lower level of response than that seen in the intravenous group. Identical patterns of response, although not of the same magnitude, were observed after both primary and secondary challenges in the two footpad groups, one infected with viable M. leprae and the other immunized with M. leprae cell extract. The secondary response after a booster dose to all these groups appeared to be an enhanced immunoglobulin M response. Control studies confirmed that the immune response was a direct result of the host-parasite interaction and that the PFC observed resulted from stimulation of antibody-forming cells by antigens of M. leprae. The similarity in time of appearance of peak PFC levels in the two footpad groups may be attributed to the live challenge passing through a latent phase. Alternatively, the challenge is known to contain a large proportion on nonviable cells, and it may also contain soluble M. leprae antigens. Studies of the cross-reactivity of the antigens have extended previous observations on antigens shared between M. leprae and other mycobacterial species. Use of the two antigen-containing fractions of the M. leprae cell extract has suggested that one of the fractions contains some shared antigens, whereas the other has an antigen specific to M. leprae.