BACKGROUND Sleep duration and quality have been associated with increased cardiovascular risk. However, large studies linking objectively measured sleep and subclinical atherosclerosis assessed in multiple vascular sites are lacking. OBJECTIVES The purpose of this study was to evaluate the association of actigraphy-measured sleep parameters with subclinical atherosclerosis in an asymptomatic middle-aged population, and investigate interactions among sleep, conventional risk factors, psychosocial factors, dietary habits, and inflammation. METHODS Seven-day actigraphic recording was performed in 3,974 participants (age 45.8 +/- 4.3 years; 62.6% men) from the PESA (Progression of Early Subclinical Atherosclerosis) study. Four groups were defined: very short sleep duration < 6 h, short sleep duration 6 to 7 h, reference sleep duration 7 to 8 h, and long sleep duration > 8 h. Sleep fragmentation index was defined as the sum of the movement index and fragmentation index. Carotid and femoral 3-dimensional vascular ultrasound and cardiac computed tomography were performed to quantify noncoronary atherosclerosis and coronary calcification. RESULTS When adjusted for conventional risk factors, very short sleep duration was independently associated with a higher atherosclerotic burden with 3-dimensional vascular ultrasound compared to the reference group (odds ratio: 1.27; 95% confidence interval: 1.06 to 1.52; p = 0.008). Participants within the highest quintile of sleep fragmentation presented a higher prevalence of multiple affected noncoronary territories (odds ratio: 1.34; 95% confidence interval: 1.09 to 1.64; p = 0.006). No differences were observed regarding coronary artery calcification score in the different sleep groups. CONCLUSIONS Lower sleeping times and fragmented sleep are independently associated with an increased risk of subclinical multiterritory atherosclerosis. These results highlight the importance of healthy sleep habits for the prevention of cardiovascular disease. (J Am Coll Cardiol 2019; 73: 134-44) (c) 2019 Published by Elsevier on behalf of the American College of Cardiology Foundation.