Background: Bronchodilator response has been noted in a significant proportion of patients with chronic obstructive pulmonary disease (COPD). However, there are also reports of a paradoxical response to β2 agonists resulting in bronchoconstriction. Asymptomatic bronchoconstriction is likely to be far more common than is symptomatic bronchoconstriction with β2 agonists, but no systematic studies have been done. We assessed the prevalence of paradoxical response in current and former smokers with and without COPD, and its radiological correlates and clinical implications. Methods: Non-Hispanic white and African-American patients (aged 45-80 years) from a large multicentre study COPDGene were classified into two groups on the basis of a paradoxical response, defined as at least a 12% and 200 mL reduction in forced expiratory volume in 1 sec (FEV1) or forced vital capacity (FVC), or both, after administration of a shortacting β2 agonist (180 μg salbutamol). Findings: Patients were recruited from January, 2008, to June, 2011. 9986 (96%) of 10 364 patients enrolled in the COPDGene study were included in the analysis population (mean age 59·6 years [SD 9·0]). Paradoxical response was noted in 453 (5%) of 9986 patients and the frequency was similar in patients with COPD (198 [4%] of 4439) and smokers without airflow obstruction (255 [5%] of 5547). Compared with white patients, a paradoxical response was twice as common in African-American patients (227 [7%] of 3282 vs 226 [3%] of 6704; p<0·0001). In the multivariate analyses, African-American ethnic origin (adjusted odds ratio 1·89, 95% CI 1·50-2·39; p<0·0001), less emphysema (0·96, 0·92-0·99; p=0·023), and increased wall-area percentage of the segmental airways (1·04, 1·01-1·08; p=0·023) were independently associated with a paradoxical response. A paradoxical response was independently associated with worse dyspnoea (adjusted β for Modified Medical Research Council Dyspnoea Scale 0·12 [95% CI 0·00 to 0·24]; p=0·05), lower 6 min walk distance (-45·8 [-78·5 to -13·2]; p=0·006), higher Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) index (0·31 [0·19 to 0·43]; p<0·0001), and a greater frequency of severe exacerbations (increased by a factor of 1·35, 1·00-1·81; p=0·048). Interpretation: Paradoxical response to β2 agonists is associated with respiratory morbidity and is more common in African-Americans. These findings might have implications for the use of β2agonists in some patients. Funding: National Institutes of Health.