Background: Platelet activation reduces pulmonary microvascular blood flow and contributes to inflammation; these factors have been implicated in the pathogenesis of COPD and emphysema. We hypothesized that regular use of aspirin, a platelet inhibitor, would be associated with a slower progression of emphysema-like lung characteristics on CT imaging and a slower decline in lung function. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants 45 to 84 years of age without clinical cardiovascular disease from 2000 to 2002. The MESA Lung Study assessed the percentage of emphysema-like lung below –950 Hounsfield units (“percent emphysema”) on cardiac (2000-2007) and full-lung CT scans (2010-2012). Regular aspirin use was defined as 3 or more days per week. Mixed-effect models adjusted for demographics, anthropometric features, smoking, hypertension, angiotensin-converting enzyme inhibitor or angiotensin II-receptor blocker use, C-reactive protein levels, sphingomyelin levels, and scanner factors. Results: At baseline, the 4,257 participants' mean (± SD) age was 61 ± 10 years, 54% were ever smokers, and 22% used aspirin regularly. On average, percent emphysema increased 0.60 percentage points over 10 years (95% CI, 0.35-0.94). Progression of percent emphysema was slower among regular aspirin users compared with patients who did not use aspirin (fully adjusted model: –0.34% /10 years, 95% CI, –0.60 to –0.08; P =.01). Results were similar in ever smokers and with doses of 81 and 300 to 325 mg and were of greater magnitude among those with airflow limitation. No association was found between aspirin use and change in lung function. Conclusions: Regular aspirin use was associated with a more than 50% reduction in the rate of emphysema progression over 10 years. Further study of aspirin and platelets in emphysema may be warranted.