The non-lab Framingham algorithm, which substitute body mass index for lipids in the laboratory based (lab-based) Framingham algorithm, has been validated among African Americans (AAs). However, its cost-effectiveness and economic tradeoffs have not been evaluated. This study examines the incremental cost-effectiveness ratio (ICER) of two cardiovascular disease (CVD) prevention programs guided by the non-lab versus lab-based Framingham algorithm. We simulated the World Health Organization CVD prevention guidelines on a cohort of 2690 AA participants in the Atherosclerosis Risk in Communities (ARIC) cohort. Costs were estimated using Medicare fee schedules (diagnostic tests, drugs & visits), Bureau of Labor Statistics (RN wages), and estimates for managing incident CVD events. Outcomes were assumed to be true positive cases detected at a data driven treatment threshold. Both algorithms had the best balance of sensitivity/specificity at the moderate risk threshold (>10% risk). Over 12years, 82% and 77% of 401 incident CVD events were accurately predicted via the non-lab and lab-based Framingham algorithms, respectively. There were 20 fewer false negative cases in the non-lab approach translating into over $900,000 in savings over 12years. The ICER was −$57,153 for every extra CVD event prevented when using the non-lab algorithm. The approach guided by the non-lab Framingham strategy dominated the lab-based approach with respect to both costs and predictive ability. Consequently, the non-lab Framingham algorithm could potentially provide a highly effective screening tool at lower cost to address the high burden of CVD especially among AA and in resource-constrained settings where lab tests are unavailable.