OBJECTIVES: In randomized clinical trials, evolocumab has shown marked reductions in low-density lipoprotein cholesterol (LDL-C) levels, a major risk factor of cardiovascular (CV) events. This analysis assesses the cost-effectiveness (CE) of evolocumab for lowering LDL-C in patients with high CV risk from the Spanish National Health System perspective. METHODS: A Markov cohort state-transition model assessed the CE of evolocumab added to standard of care (SOC) compared to SOC, assuming lifetime treatment. SOC was defined as either statins or no treatment in case of statin intolerance (SI). Cohorts with baseline LDL-C ≥100 mg/dL and heterozygous familial hypercholesterolemia (HeFH) or CV event history without/with SI were considered. Lifetime CV event rates (acute coronary syndrome, ischemic stroke, heart failure, CV death) were predicted either (a) using risk equations considering local risk factors [SAFEHEART] and adjusted to reflect the increased risk of HeFH patients or (b) using CV event rates directly observed in local registries [SIDIAP] for patients with CV event history. LDL-C relative reductions from evolocumab clinical trials were translated into CV event reductions using the rate ratios per mmol/L published from a large meta-analysis of statin trials [CTTC]. RESULTS: Predicted per patient-year rates of (non-fatal; fatal) CV events were HeFH (2.2; 0.8), CV event history (1.1; 0.6), CV event history with SI (1.3; 0.7) for SOC and HeFH (1.2; 0.6), CV event history (0.7; 0.5), CV event history with SI (0.8; 0.6) for evolocumab added to SOC. Evolocumab added to SOC was associated with HeFH (Δcost: €65,369; ΔQALY: 2.12; ICER: €30,893), CV event history (Δcost: €42,266; ΔQALY: 0.93; ICER: €45,340), CV event history with SI (Δcost: €38,482; ΔQALY: 1.16; ICER: €33,191). CONCLUSIONS: Among patients with HeFH or CV event history without/with SI, evolocumab added to SOC may provide a CE option for lowering LDL-C, considering the commonly accepted thresholds in Spain of €30,000-€45,000 per ΔQALY.