Rationale: Cardiovascular disease is a common comorbidity in patients with chronic obstructive pulmonary disease (COPD). Although beta-blockers can be used safely in COPD, concerns remain regarding safety and efficacy interactions in patients using concomitant inhaled long-acting beta-agonists. Objectives: To compare the differential effects of long-acting beta agonist or inhaled corticosteroid use on clinical outcomes in patients with heightened cardiovascular risk treated and not treated with beta-blockers. Methods: We examined data from 16,485 participants in the Study to Understand Mortality and MorbidITy in COPD (SUMMIT) who were randomized to once daily inhaled fluticasone furoate (FF), vilanterol (VI), their combination (FF/VI), or placebo and examined the associations between treatment allocation and lung function, COPD exacerbations, cardiovascular events, and all-cause mortality stratified by baseline beta-blocker therapy. Results: Baseline beta-blocker therapy was used by 31% (n=5,159) of SUMMIT participants. There was no evidence of an interaction between baseline beta-blocker therapy and the association between inhaled treatments and FEV1 at 3 months (p=0.27), 6 months (p=0.14), or 12 months (p=0.33). The placebo-adjusted mean difference in post-bronchodilator FEV1 at 3 months in the VI alone group was 58 mL [95% confidence interval (CI) 38, 78] in those taking baseline beta-blocker therapy, and 51 mL [95%CI 38, 65], in those not taking baseline beta-blocker therapy. The placebo-adjusted mean difference in post-bronchodilator FEV1 at 3 months in the FF/VI group was 85 mL [95%CI 65, 105] in those taking baseline beta-blocker therapy, and 68 mL [95%CI 54, 82] in those not taking baseline beta-blocker therapy. Overall, there was no evidence of interactions by randomized treatment, including VI alone or in combination with FF, for COPD exacerbations (p=0.18), cardiovascular composite events (p=0.33), and all-cause mortality (p=0.41). Conclusions: There is no evidence to suggest that baseline beta-blocker therapy reduces the respiratory benefits or increases the cardiovascular risk of inhaled long-acting beta-agonists in patients with COPD and heightened cardiovascular risk. Clinical trial registered with ClinicalTrials.gov (NCT01313676