Rationale: Short-acting ₂-agonists (SABAs) are one of the mainstays of bronchodilator strategy for exacerbations of chronic obstructive pulmonary disease (COPD). The assessment of pulmonary gas exchange after salbutamol in COPD severe exacerbations remains unknown. Objectives: We investigated whether the effects of nebulized salbutamol at COPD severe exacerbations are associated with further pulmonary gas exchange worsening. Methods: We examined severe COPD patients when hospitalized for exacerbation (n, 9), and while in stable convalescence. We assessed spirometry, arterial blood gases, systemic hemodynamics and ventilation-perfusion (V_A/Q) relationships 30 and 90 min after 5.0 mg salbutamol. Results: At exacerbation, compared to baseline, 30 min after salbutamol cardiac output increased (Q_T) (from 6.5±(SE)0.4 to 7.3±0.5 L.min_-1) (p<0.03) alone, without inducing changes in gas exchange indices. When in convalescence, compared to baseline, 30 min after salbutamol Q_T (from 5.7±0.5 to 7.0±0.6 L.min^-1) and oxygen consumption (from 211±12 to 232±11 mL.min^-1) increased (p<0.002 each) while PaO₂ decreased (from 71±4 to 63±3 mmHg) and AaPO₂ increased due to increased perfusion of low V_A/Q ratio regions (from 4.5±2.6 to 9.6±4.1% of Q_T) (p<0.05); SaO₂ (93±2%) and PaCO₂ (43±2 mmHg) remained unchanged. This deleterious gas exchange response persisted at 90 min. Conclusions: At exacerbation, salbutamol does not aggravate pulmonary gas exchange abnormalities. When in convalescence, however, baseline lung function improvement was associated with a detrimental gas exchange response to salbutamol resulting in further V_A/Q imbalance and small decreased PaO₂ compounded by small increases in Q_T and VO₂.