Authenic tracheobronchial secretions/exudates (TBSE) were aspirated under direct vision via a sterile catheter passed through a fiberoptic bronchoscope from patients with chronic obstructive pulmonary disease complicated by chronic bronchitis. TBSE, saliva and blood were obtained during long-term administration of trimethoprim-sulfamethoxazole (TMP-SMX) and were assayed for drug content. Before and during treatment TBSE were cultured qualitatively and quantitatively for aerobic and anaerobic bacteria, fungi, mycoplasmas and viruses. Treatment with TMP-SMX was associated with a decrease in the recovery of Hemophilus influenzae, H. parainfluenzae, Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis; however, little effect was observed on the typically nonpathogenic aerobic and anaerobic bacteria of the upper respiratory tract. TMP was found in saliva at concentrations greater than in serum. Both TMP and SMX entered TBSE in absolute and relative concentrations sufficient to take advantage of the potential for synergy against susceptible microorganisms. Patient tolerance of TMP-SMX was generally good and several patients reported a decrease in production of sputum during treatment.