OBJECTIVES: Treatment with the PCSK9 inhibitor evolocumab in randomized trials has resulted in significant reductions in low-density lipoprotein cholesterol (LDL-C). The objective of this study was to assess the cost-effectiveness and economic value of evolocumab for payers in the United States. METHODS: A cohort state transition model estimated the cost-effectiveness of evolocumab added to standard of care (SOC) vs SOC alone from a US payer perspective in a lifetime horizon. The model assessed cost-effectiveness in patients with baseline LDL-C >100 mg/dL and heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic CVD (ASCVD) with or without statin intolerance. Primary and recurrent CVD event rates were predicted based on standard risk equations using population-specific, trial-based mean risk factors and calibrated against observed rates from real-world data. The predicted 10-year risk of experiencing ≥1 CVD event per person was 51% in HeFH, 44% in ASCVD without statin intolerance, and 51% in ASCVD with statin intolerance. LDL-C reduction in the model was derived from relative reductions from evolocumab phase 3 randomized trials. The model also considered the estimated LDL-C lowering effect on CVD event rates from a large statin-trial meta-analysis. Costs (commercial US payer) and utilities were gathered from published sources. RESULTS: Evolocumab treatment was associated with increased cost, survival, and quality of life: HeFH (incremental cost $153,289; incremental quality-adjusted life years [QALY] 2.02; ICER $75,863/QALY); ASCVD without statin intolerance ($158,307; 1.12; $141,699/QALY); ASCVD with statin intolerance ($136,903; 1.36; $100,309/QALY). Evolocumab met the American College of Cardiology/American Heart Association (intermediate value) and World Health Organization (3 × GDP) cost-effectiveness thresholds in all populations evaluated. Sensitivity and scenario analyses confirmed that model results were robust to changes in model parameters. CONCLUSIONS: Among patients with HeFH and ASCVD with/without statin intolerance, evolocumab added to SOC may provide a cost-effective treatment option for lowering LDL-C.