© 2016 American Medical Association. All rights reserved. Importance Although cardiorespiratory fitness (CRF) is prognostic in older adults, the effect of CRF during early adulthood on long-term cardiovascular structure, function, and prognosis is less clear. Objective To examine whether CRF in young adults is associated with long-term clinical outcome and subclinical cardiovascular disease (CVD). Design, Setting, and Participants Prospective study of 4872 US adults aged 18 to 30 years who underwent treadmill exercise testing at a baseline study visit from March 25, 1985, to June 7, 1986, and 2472 individuals who underwent a second treadmill test 7 years later. Median follow-up was 26.9 years, with assessment of obesity, left ventricular mass and strain, coronary artery calcification (CAC), and vital status and incident CVD. Follow-up was complete on August 31, 2011, and data were analyzed from recruitment through the end of follow-up. Main Outcomes and Measures The presence of CACwas assessed by computed tomography at years 15 (2000-2001), 20 (2005-2006), and 25 (2010-2011), and left ventricular mass was assessed at years 5 (1990-1991) and 25 (with global longitudinal strain). Incident CVD and all-cause mortality were adjudicated. Results Of the 4872 individuals, 273 (5.6%) died and 193 (4.0%) experienced CVD events during follow-up. After comprehensive adjustment, each additional minute of baseline exercise test duration was associated with a 15%lower hazard of death (hazard ratio [HR], 0.85; 95%CI, 0.80-0.91; P <.001) and a 12%lower hazard of CVD (HR, 0.88; 95%CI, 0.81-0.96; P =.002). Higher levels of baseline CRF were associated with significantly lower left ventricular mass index (β =.0.24; 95%CI,.0.45 to.0.03; P =.02) and significantly better lobal longitudinal strain (β =.0.09; 95%CI,.0.14 to.0.05; P <.001) at year 25. Fitness was not associated with CAC. A 1-minute reduction in fitness by year 7 was associated with 21% and 20%increased hazards of death (HR, 1.21; 95%CI, 1.07-1.37; P =.002) and CVD (HR, 1.20; 95%CI, 1.06-1.37; P =.006), respectively, along with a more impaired strain (β = 0.15; 95%CI, 0.08-0.23; P <.001). No association between change in fitness and CAC was found. Conclusions and Relevance Higher levels of fitness at baseline and improvement in fitness early in adulthood are favorably associated with lower risks for CVD and mortality. Fitness and changes in fitness are associated withmyocardial hypertrophy and dysfunction but not CAC. Regular efforts to ascertain and improve CRF in young adulthood may play a critical role in promoting cardiovascular health and interrupting early CVD pathogenesis.