Six months of twice weekly directly observed isoniazid and rifam-picin treatment of latent tuberculosis (TB) infection was implemented to improve the outcome of treatment. A total of 591 infected aborigines without previous tuberculosis or treatment of latent TB infection received twice weekly isoniazid and rifampicin for 6 mo from 1992 to 1995. The outcome was compared with 403 infected aborigines without previous tuberculosis or treatment of latent TB infection who received self-administered isoniazid daily for 1 yr from 1986 to 1989. Of patients, 487 (82%) completed the twice weekly 6-mo regimen compared with 77 (19%) who completed the daily 12-mo regimen. The main reason for incomplete treatment was default. Both groups were followed over a 6-yr period. The rate of tuberculosis in the twice-weekly isoniazid and rifampicin-treated patients was 0.9/1,000 patient-years compared with 9/1,000 patient-years in the daily isoniazid-treated patients. The rate of side effects was higher for directly observed treatment patients, 136/1,000 patient-years of drugs, compared with 39/ 1,000 patient-years for self-administered treatment patients. Life-threatening side effects such as skin allergic reactions and hepatitis were the same in both groups. A regimen of 52 doses of directly observed twice weekly isoniazid and rifampicin is an effective and well-tolerated regimen to improve the outcome of the treatment of latent tuberculosis infection in a population with a high rate of default with daily self-administered isoniazid.