Objective To evaluate the relationship between small airway disease and the progression of chronic obstructive pulmonary disease (COPD), and explore the application value of high resolution computed tomography (HRCT) and impulse oscillometry system (IOS) in assessing small airways in COPD patients. Methods A total of 132 stable COPD patients and 43 healthy controls volunteered to take the IOS and pulmonary function test. The correlations between resonance frequency (Fres), small airway resistance (R5-R20) and spirometry were analyzed. The patients were also examined by HRCT to measure the thickness of the third generation of apical bronchus of the right upper lobe (WT), the adjacent pulmonary artery diameter (BWT) and the degree of emphysema (LAA%). The ratio of WT to BWT (WT/BWT) was calculated to estimate bronchial wall thickening. Relationships between WT/BWT, emphysema and spirometry, IOS were also studied. Results There were negative correlations between Fres and FEV1%pred, FEF25%-75%%pred, FEF50%%pred (r=-0.694, -0.561, -0.619, all P<0.01). R5-R20 was negatively associated with FEV1%pred, FEF25%-75%%pred and FEF50%%pred as well (r=-0.622, -0.537, -0.560, P<0.01). The analysis of receiver operating characteristic curve showed larger areas under the Fres and R5-R20 curves, and the cutoff points to diagnose COPD were 13.93 Hz and 0.055 kPa·L-1·s-1, respectively. LAA% and WT/BWT increased with airflow limitation (F=4.859, 9.792, both P<0.01). WT/BWT was negatively associated with FEV1%pred (r=-0.329, P<0.05), and positively with Fres and R5-R20 (r=0.259, 0.241, P<0.05). LAA% was negatively correlated with FEV1%pred (r=-0.566, P<0.05), and correlations also existed between LAA% and physiological indices of small airways such as FEF25%-75%%pred, FEF50%%pred, Fres and R5-R20 (r=-0.456, -0.474, 0.466, 0.340, all P<0.05). Conclusions The peripheral airway resistance is increased and bronchial wall thickens in patients with COPD, and these changes can reflect the severity of the disease. Small airway disease measured by HRCT and IOS are related to the spirometric indices, and represent the structural and functional changes of small airways. Combinations of these two tests with spirometry will be possible to make early diagnosis and better control the disease.