Background-Evidence shows that healthy diet, exercise, smoking interventions, and stress reduction reduce cardiovascular disease risk. We aimed to compare the effectiveness of these lifestyle interventions for individual risk profiles and determine their rank order in reducing 10-year cardiovascular disease risk. Methods and Results-We computed risks using the American College of Cardiology/American Heart Association Pooled Cohort Equations for a variety of individual profiles. Using published literature on risk factor reductions through diverse lifestyle interventions-group therapy for stopping smoking, Mediterranean diet, aerobic exercise (walking), and yoga-we calculated the risk reduction through each of these interventions to determine the strategy associated with the maximum benefit for each profile. Sensitivity analyses were conducted to test the robustness of the results. In the base-case analysis, yoga was associated with the largest 10-year cardiovascular disease risk reductions (maximum absolute reduction 16.7% for the highest-risk individuals). Walking generally ranked second (max 11.4%), followed by Mediterranean diet (max 9.2%), and group therapy for smoking (max 1.6%). If the individual was a current smoker and successfully quit smoking (ie, achieved complete smoking cessation), then stopping smoking yielded the largest reduction. Probabilistic and 1-way sensitivity analysis confirmed the demonstrated trend. Conclusions-This study reports the comparative effectiveness of several forms of lifestyle modifications and found smoking cessation and yoga to be the most effective forms of cardiovascular disease prevention. Future research should focus on patient adherence to personalized therapies, cost-effectiveness of these strategies, and the potential for enhanced benefit when interventions are performed simultaneously rather than as single measures.