BACKGROUND Triple inhalation therapy with tiotropium (Tio) and salmeterol/fluticasone propionate combination (SFC) is widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, the effects of triple therapy on airway structural changes remain unknown. OBJECTIVE The aim of the study was to assess the effects of Tio, salmeterol (SM), SFC and Tio plus SFC on airway dimensions in COPD. METHODS A randomized, open-label, 4-way study (n = 60) was conducted comparing 16-week treatment periods of Tio (18 μg once daily), SM (50 μg twice daily), SFC (50/250 μg twice daily) and Tio (18 μg once daily) plus SFC (50/250 μg twice daily). Airway dimensions were assessed by a validated CT technique, and airway wall area (WA) corrected for body surface area (BSA), percentage WA (WA%), wall thickness/√BSA and luminal area (Ai)/BSA at the right apical segmental bronchus were measured. Pulmonary function and the St. George's Respiratory Questionnaire (SGRQ) were evaluated. RESULTS Tio plus SFC resulted in a significant decrease in WA corrected for BSA and WA% compared with Tio, SM and SFC (p < 0.05 for all). The changes in WA% and Ai/BSA were significantly correlated with changes in forced expiratory volume in 1 s (r = -0.86, p < 0.001, and r = 0.48, p < 0.05, respectively). There were more significant improvements in SGRQ scores after treatment with triple therapy than after the 3 other treatments. CONCLUSIONS Tio plus SFC therapy is more effective than Tio, SM and SFC for reducing airway wall thickness in COPD.