Background: Beta-blockers remain underused in patients with COPD and cardiovascular disease. Aim: We compared how different inhaled therapies affect tolerability of bisoprolol and carvedilol in moderate to severe COPD. Design: A randomized, open label, cross-over study. Methods: We compared the cardiopulmonary interactions of bisoprolol 5mg qd or carvedilol 12·5 mg bid for 6 weeks in conjunction with: (a) triple: inhaled corticosteroid /long acting beta-agonist/long acting muscarinic antagonist (ICS+LABA+LAMA), (b) dual: ICS+LABA, (c) ICS alone. Results:18 patients completed, all ex-smokers, mean age 65 years, forced expiratory volume in 1 second (FEV1) 52% predicted. Bisoprolol and carvedilol produced comparable significant reduction in resting and exercise heart rate. FEV1, forced vital capacity (FVC) and lung compliance (AX) were significantly lower with carvedilol vs bisoprolol while taking concomitant ICS/LABA (P<0·05) but not ICS/LABA/LAMA. Conclusions: In summary, bisoprolol was better tolerated than carvedilol on pulmonary function at doses which produced equivalent cardiac beta-1 blockade. Worsening of pulmonary function with carvedilol was mitigated by concomitant inhaled LAMA (tiotropium) with LABA (formoterol), but not LABA alone.