We have shown that 6-month therapy with isoniazid (INH) and rifampin (RIF) is adequate for pulmonary tuberculosis when tubercle bacilli are less numerous, i.e., smear negative, culture positive. Tuberculous exudative pleural effusion contains small bacterial populations, as often demonstrated by negative smears and fewer positive cultures. Therefore, in 1980, we started treating tuberculous pleural effusion with a therapy protocol consisting of INH 300 mg plus RIF 600 mg daily for 1 month, followed by INH 900 mg plus RIF 600 mg twice weekly for another 5 months (total, 6 months). From January 1980 to September 1990, 198 patients with an average age of 62.6 years were treated in this manner. Associated pulmonary infiltration was present in 92 patients, of whom 50% yielded positive sputum cultures. Other medical conditions as "risk factors" were present in 30%. Therapy was not completed in 36 patients because of death, relocation, noncompliance, and drug side effects. Treatment failed during therapy in only 1 patient. Side effects of the drugs occurred in 13 (6.6%) patients, but major side effects were encountered in only three (1.5%), two with toxic hepatitis and one with thrombocytopenia. The full 6-month therapy was completed by 161 patients. During follow-up from 2 to 133 months (median, 46 months), none of the 161 patients had relapse. An overall success rate of 99% was achieved in 162 patients with only 1 failure during therapy. Thus, 6-month therapy with INH plus RIF is adequate in tuberculous exudative pleural effusion, even when associated with smear-negative (3 specimens) culture-positive pulmonary tuberculosis.