BACKGROUND: Circulating galectin-3 levels provide prognostic information in patients with established heart failure (HF), but the associations between galectin-3 levels and other incident cardiovascular events in asymptomatic individuals at midlife and when remeasured ≈15 years later are largely uncharacterized. METHODS AND RESULTS: Using multivariable Cox proportional hazards models, we identified associations between plasma galectin-3 levels (hazard ratio [HR] per 1 SD increase in natural log galectin-3) and incident coronary heart disease, ischemic stroke, HF hospitalization, and total mortality in ARIC (Atherosclerosis Risk in Communities) participants free of cardiovascular disease at ARIC visit 4 (1996–1998; n=9247) and at ARIC visit 5 (2011–2013; n=4829). Higher galectin-3 level at visit 4 (median age 62) was independently associated with incident coronary heart disease (adjusted HR, 1.30; 95% CI, 1.06–1.60), ischemic stroke (HR, 1.42; 95% CI, 1.01–2.00), HF (HR, 1.44; 95% CI, 1.17–1.76), and mortality (HR, 1.56; 95% CI, 1.35–1.80). At visit 5 (median age, 74), higher galectin-3 level was associated with incident HF (HR, 1.93; 95% CI, 1.15–3.24) and total mortality (HR, 1.70; 95% CI, 1.15–2.52), but not coronary heart disease or stoke. Individuals with the greatest increase in galectin-3 levels from visit 4 to visit 5 were also at increased risk of incident HF and total mortality. CONCLUSIONS: In a large, biracial community-based cohort, galectin-3 measured at midlife and older age was associated with increased risk of cardiovascular events. An increase in galectin-3 levels over this period was also associated with increased risk.