Copyright © 2017 by the American Thoracic Society. Rationale: Handgrip strength (HGS) predicts mortality in the elderly, but its determinants and clinical significance in chronic obstructive pulmonary disease (COPD) has not been defined. Objectives: We tested associations of HGS with pectoralis muscle area (PMA), subcutaneous adipose tissue (SAT), imaging characteristics, and lung function in smokers with COPD, and evaluated the cross-sectional and longitudinal associations of HGS with acute respiratory events. Methods: We analyzed demographic, clinical, spirometry, HGS, and imaging data of 272 subjects with COPD, obtaining measures of airway thickness, emphysema, PMA, and SAT from chest computed tomography scans. We tested associations of lung function and imaging characteristics with HGS, using linear models. HGS association to acute respiratory events at enrollment and during follow-up (mean, 2.6 years) was analyzed using adjusted logistic models. Results:HGScorrelated with PMA, SAT, forced expiratory volume, and airway thickness, but not with body mass index or emphysema severity. In adjusted regression models,HGSwas directly (b, 1.5; 95% confidence interval [CI], 0.1-3.0) and inversely (b, 23.3; 95% CI, 25.1 to 20.9) associated with one standard deviation of PMA and SAT, respectively, independent of body mass index and emphysema. In regression models adjusted for age, sex, body mass index, race, pack-years smoked, current smoking, chronic bronchitis, FEV1% predicted, emphysema, and airway metrics, HGS was associated with exacerbation risk; in cross-sectional analyses, there was an increment of 5% in the risk of exacerbations for each 1-kg decrement in HGS (risk ratio, 1.05; 95% CI, 1.01-1.08), and there was a similar risk during follow-up (risk ratio, 1.04; 95% CI, 1.01-1,07). Conclusions: In ever-smokers with COPD, HGS is associated with computed tomography markers of body composition and airway thickness, independent of body mass index and emphysema. Higher HGS is associated with lower exacerbation frequency.