Study objective: The standard daily dose of rifampin in directly observed treatment of Mycobacterium tuberculosis (TB) is 600 mg, taken orally. The purpose of this study was to assess the efficacy of standard dose rifampin therapy in patients who were slow to respond to routine directly observed therapy (DOT). Methods: Patients with non-drug-resistant pulmonary TB who were receiving 600 mg of oral rifampin by DOT were eligible for inclusion. Patients were deemed slow to respond if their sputum smears and cultures remained positive for M tuberculosis and if the patient’s condition did not improve clinically or radiographically after 3 months of treatment. Serum rifampin levels were ascertained to determine the adequacy of the standard rifampin dosing. Patients with subtherapeutic blood levels had their rifampin dose increased to 900 mg, and rifampin levels were repeated. Rifampin dosage was increased again if blood levels were still subtherapeutic. No antitubercular medications were added to the treatment regimen. The total weekly dose of the other standard treatment drugs was not increased. Results: Of 124 new patients with active pulmonary TB, 6 patients were identified as slow to respond to the standard antitubercular DOT. All six patients had subtherapeutic serum rifampin levels. All six patients responded clinically, radiographically, and mycobacteriologically after an increase in rifampin dosage to reach target drug blood level. Conclusions: Standard dosing with rifampin resulted in a poor clinical response and subtherapeutic serum levels in six patients. Increasing the dosage of rifampin improved the outcome without additional side effects. In TB patients who are slow to respond to standard treatment, an inadequate dose of rifampin should be suspected. Current antituberculer drug administration does not include adjusted dosage for rifampin.