Copyright © 2016 American Medical Association. All rights reserved. Importance: Whether sustained physical activity prevents cardiovascular disease (CVD) events in older adults is uncertain. Objective: To test the hypothesis that cardiovascular morbidity and mortality would be reduced in participants in a long-term physical activity program. Design, Setting, and Participants: The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial. Participants were recruited at 8 centers in the United States. We randomized 1635 sedentary men and women aged 70 to 89 years with a Short Physical Performance Battery (SPPB) score of 9 or less but able to walk 400 m. Interventions: The physcial activity (PA) intervention was a structured moderate-intensity program, predominantly walking 2 times per week on site for 2.6 years on average. The successful aging intervention consisted of weekly health education sessions for 6 months, then monthly. Main Outcomes and Measures: Total CVD events, including fatal and nonfatal myocardial infarction, angina, stroke, transient ischemic attack, and peripheral artery disease, were adjudicated by committee, and silent myocardial infarction was assessed by serial electrocardiograms. A limited outcome of myocardial infarction, stroke, and CVD death was also studied. Outcome assessors and adjudicators were blinded to intervention assignment. Results: The 1635 LIFE study participants were predominantly women (67%), with a mean (SD) age of 78.7 (5.2) years; 20% were African-American, 6% were Hispanic or other race or ethnic group, and 74%were non-Latino white. New CVD events occurred in 121 of 818 PA participants (14.8%) and 113 of 817 successful aging participants (13.8%) (HR, 1.10; 95%CI, 0.85-1.42). For the more focused combined outcome of myocardial infarction, stroke, or cardiovascular death, rates were 4.6% in PA and 4.5% in the successful aging group (HR, 1.05; 95%CI, 0.67-1.66). Among frailer participants with an SPPB score less than 8, total CVD rates were 14.2% in PA vs 17.7% in successful aging (HR, 0.76; 95%CI, 0.52-1.10), compared with 15.3% vs 10.5% among those with an SPPB score of 8 or 9 (HR, 1.59; 95%CI, 1.09-2.30) (P for interaction = .006). With the limited end point, the interaction was not significant (P = .59), with an HR of 0.94 (95%CI, 0.50-1.75) for an SPPB score less than 8 and an HR of 1.20 (95%CI, 0.62-2.34) for an SBBP score of 8 or 9. Conclusions and Relevance: Among participants in the LIFE Study, an aerobically based, moderately intensive PA program was not associated with reduced cardiovascular events in spite of the intervention's previously documented ability to prevent mobility disability.