We describe a patient with drug-resistant chronic tuberculous empyema in whom substantial differences between achievable pleural fluid and serum drug concentrations were displayed. The ratio of maximum concentration in pleural fluid to serum was especially low for rifampin (4%) but was also low for streptomycin (34%) and ofloxacin (48%). Subtherapeutic drug concentrations in the pleural fluid may have contributed to acquisition of drug resistance in this case.