Background: Ventilatory inefficiency contributes to exercise intolerance in chronic obstructive pulmonary disease (COPD). The intercept of the minute ventilation (V-E) vs. carbon dioxide output (VCO2) plot is a key ventilatory inefficiency parameter. However, its relationships with lung hyperinflation (LH) and airflow limitation are not known. This study aimed to evaluate correlations between the V-E/VCO2 intercept and LH and airflow limitation to determine its physiological interpretation as an index of functional impairment in COPD. Methods: We conducted a retrospective analysis of data from 53 COPD patients and 14 healthy controls who performed incremental cardiopulmonary exercise tests (CPETs) and resting pulmonary function assessment. Ventilatory inefficiency was represented by parameters reflecting the V-E/VCO2 nadir and slope (linear region) and the intercept of V-E/VCO2 plot. Their correlations with measures of LH and airflow limitation were evaluated. Results: Compared to control, the slope (30.58 +/- 3.62, P<0.001) and intercept (4.85 +/- 1.11 L/min, P<0.05) were higher in COPDstages1-2, leading to a higher nadir (31.47 +/- 4.47, P<0.01). Despite an even higher intercept in COPDstages3- 4 (7.16 +/- 1.41, P< 0.001), the slope diminished with disease progression (from 30.58 +/- 3.62 in COPDstages1-2 to 26.84 +/- 4.96 in COPDstages3-4, P<0.01). There was no difference in nadir among COPD groups and higher intercepts across all stages. The intercept was correlated with peak V-E/maximal voluntary ventilation (MVV) (r=0.489, P<0.001) and peak VO2/Watt (r=0.354, P=0.003). The intercept was positively correlated with residual volume (RV) % predicted (r=0.571, P<0.001), RV/total lung capacity (TLC) (r=0.588, P<0.001), peak tidal volume (V-T)/FEV1 (r=0.482, P<0.001) and negatively correlated with rest inspiratory capacity (IC)/TLC (r=- 0.574, P<0.001), peak V-T/TLC (r=- 0.585, P<0.001), airflow limitation forced expiratory volume in 1 s (FEV1) % predicted (r=-0.606, P<0.001), and FEV1/forced vital capacity (FVC) (r=-0.629, P<0.001). Conclusions: V-E/VCO2 intercept was consistently correlated with worsening static and dynamic LH, pulmonary gas exchange, and airflow limitation in COPD. The V-E/VCO2 intercept emerged as a useful index of ventilatory inefficiency in COPD patients.