Abstract Background/Aim Targeting PCSK9 inhibitors (PCSK9i) to patients with high LDL-cholesterol (LDL-C) as well as a high cardiovascular event rate yields the highest therapeutic effect and is thus reasonable from a health economic perspective. The current European dyslipidaemia guideline determines PCSK9i eligibility solely by LDL-C, whereas guidelines from the US/the UK additionally use a set of clinical risk factors. Such selection criteria require evaluation. Methods We determined the cardiovascular event rate and calculated the cost/preventable cardiovascular event for PCSK9i initiation in the target populations according to three scenarios: (i) European Society of Cardiology (ESC) 2019 dyslipidaemia guideline (PCSK9i recommended for all patients with residual LDL-C >55 mg/dl), (ii) American Heart Association/American College of Cardiology (AHA/ACC) 2018 cholesterol guideline (use of PCSK9i restricted to patients with residual LDL-C >70 mg/dl and clinical risk factors) and (iii) UK National Institute for Health and Care (NICE) recommendation (use of PCSK9i restricted to patients with residual LDL-C >155 mg/dl or >135 mg/dl with clinical risk factors). A Monte Carlo simulation taking into account statin intolerance was used to simulate uptitration of lipid lowering medications according to the different scenarios. Analyses were based on patients with atherosclerotic cardiovascular disease (ASCVD) from a contemporary all-comers cohort recruited at a large tertiary care center in Germany. Major adverse cardiovascular events (MACE, defined as the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) were recorded over a median follow-up of 4.2 years. Results We included 1922 patients with ASCVD (mean age 69.3 years, median baseline LDL-C 86.0 mg/dl, 75.0% male). Eligibility for PCSK9i was simulated to be 39.6% (ESC 2019), 6.2% (AHA/ACC 2018) and 1.4% (NICE). The 3 year cardiovascular event rates in the corresponding PCSK9i target populations were 11.4%, 13.8% and 13.8% respectively. Event rate differences were driven by a higher rate of non-fatal myocardial infarction in the risk-based target populations (5.2%, 8.2%, 7.2%). Annual cost/preventable event differed by up to a factor 3 (689,000 €, 515,000 € and 215,000 €), driven mainly by pre-PCSK9i LDL-C levels in the different target populations (68.8 mg/dl, 76.0 mg/dl and 182.7 mg/dl). (Table 1) Conclusion The AHA/ACC and NICE guidelines, based on both residual LDL-C and clinical risk factors, reduced the eligibility for PCSK9i as well as the cost/preventable cardiovascular event compared to the ESC guideline. However, the clinical criteria used for risk classification yielded limited discrimination for the identification of subpopulations at highest cardiovascular risk. Development of accurate risk prediction tools and their integration into risk-based allocation strategies, both requisites for a cost-effective use of PCSK9i, remain a challenge.Table 1