We hypothesized that combined salbutamol and external positive end-expiratory pressure (PEEPe) may present additive benefits in chronic obstructive pulmonary disease (COPD) exacerbation. In 10 anesthetized, mechanically ventilated, and bronchodilator-responsive COPD patients exhibiting moderate intrinsic PEEP (PEEPi), we assessed respiratory system (rs) mechanics, hemodynamics, and gas exchange at (a) baseline (zero PEEPe [ZEEPe]), (b) 30 min after 5 mg of nebulized salbutamol administration (ZEEPe-S), (c) 30 min after setting PEEPe at baseline PEEPi level (PEEPe), and (d) 30 min after 5 mg of nebulized salbutamol administration with PEEPe maintained unchanged (PEEPe-S). Return of determined variable values to baseline values was confirmed before PEEPe application. Relative to ZEEPe, (a) at ZEEP-S, PEEPi (4.8 ± 0.7 versus 7.0 ± 1.1 cm H2O), functional residual capacity change (115.6 ± 23.1 versus 202.1 ± 46.0 mL), minimal rs (airway) resistance (9.3 ± 1.4 versus 11.8 ± 2.2 cm H2O·L−1·s−1), and additional rs resistance (5.2 ± 1.4 versus 7.2 ± 1.3 cm H2O·L−1·s−1) were reduced (P < 0.01), and hemodynamics were improved; (b) at PEEPe, PEEPi (3.7 ± 1.3 cm H2O) was reduced (P < 0.01), and gas exchange was improved; and (c) at PEEPe-S, PEEPi (2.0 ± 1.2 cm H2O) was minimized, and rs mechanics (static rs elastance included), hemodynamics, and gas exchange were improved. Conclusively, in carefully preselected COPD patients, bronchodilation/PEEPe exhibits additive benefits.