The toxicity of the potent tuberculocidal agent, isoniazid, is mediated by the heme-containing enzyme, catalase-peroxidase, encoded by the katG gene. Although isoniazid has been used for the treatment of leprosy, it is shown here that the katG gene of Mycobacterium leprae is a pseudogene, which has probably been inactivated by multiple mutations. Inactive genes were detected by the polymerase chain reaction in several isolates of M. leprae, of different geographical origins, and attempts to complement an isoniazid-resistant strain of Mycobacterium smegmatis with the katG pseudogene were unsuccessful. Isoniazid is thus likely to be of no therapeutic benefit to leprosy patients.