The cross-reactivity in vitro between Mycobacterium leprae and M. tuberculosis was studied in 41 Aboriginal Australians with leprosy, 78 uninfected contacts of leprosy patients and 38 control individuals. A vigorous T cell response to epitopes cross-reactive between these two mycobacteria was found for healthy uninfected contacts or non-contacts (controls) of leprosy patients, but not for the patients themselves. The data suggest that a vaccine based on antigen shared between M. leprae and other mycobacteria is unlikely to be useful in preventing leprosy. Further studies of responses in vitro to purified T cell-reactive antigens would be useful in designing newer vaccines for more widespread field studies of leprosy prevention.