Weak of non-reactors to M. leprae (529), including Mitsuda-negative contacts and patients with leprosy were vaccinated once or repeatedly, as necessary, with a mixture of 6 .times. 108 purified, heat-killed M. leprae and 0.01 mg-0.2 mg of viable BCG. Clinical, histopathological and immunological criteria were used to evaluate the response of these individuals. Clinical changes, including sharper definition of borders and progressive flattening and regression of lesions, were observed in 57% of the active lepromatous/lepromatous cases and 76% of the active borderline/lepromatous cases. Histopathological study revealed infiltration of the lesions by mononuclear cells, appearance of epithelioid differentiation and fragmentation of the microorganisms. Delayed-type skin tests with soluble antigen from purified M. leprae became positive in significant numbers of each group studied. Thus, combined immunotherapy is efficacious in low-resistance forms of leprosy and is potentially useful in the immunoprophylaxis of the disease.