Background Epidemiologic studies on the relationship between avocado intake and long-term cardiovascular disease (CVD) risk are lacking. Methods and Results This study included 68 786 women from the NHS (Nurses' Health Study) and 41 701 men from the HPFS (Health Professionals Follow-up Study; 1986-2016) who were free of cancer, coronary heart disease, and stroke at baseline. Diet was assessed using validated food frequency questionnaires at baseline and then every 4 years. Cox proportional hazards regressions were used to estimate hazard ratios and 95% CIs. A total of 14 274 incident cases of CVD (9185 coronary heart disease events and 5290 strokes) were documented over 30 years of follow-up. After adjusting for lifestyle and other dietary factors, compared with nonconsumers, those with analysis-specific higher avocado intake (≥2 servings/week) had a 16% lower risk of CVD (pooled hazard ratio, 0.84; 95% CI, 0.75-0.95) and a 21% lower risk of coronary heart disease (pooled hazard ratio, 0.79; 95% CI, 0.68-0.91). No significant associations were observed for stroke. Per each half serving/day increase in avocado intake, the pooled hazard ratio for CVD was 0.80 (95% CI, 0.71-0.91). Replacing half a serving/day of margarine, butter, egg, yogurt, cheese, or processed meats with the equivalent amount of avocado was associated with a 16% to 22% lower risk of CVD. Conclusions Higher avocado intake was associated with lower risk of CVD and coronary heart disease in 2 large prospective cohorts of US men and women. The replacement of certain fat-containing foods with avocado could lead to lower risk of CVD.