BACKGROUND: Familial hypercholesterolemia (FH) is a common autosomal dominant disorder associated with a substantially increased risk of atherosclerotic cardiovascular disease. In low- and middle-income countries (LMICs), universal FH screening is often impractical, highlighting the need for targeted screening strategies embedded within existing health systems. OBJECTIVES: To evaluate the detection yield and real-world implementation feasibility of a stepwise targeted FH screening strategy in a resource-limited setting. METHODS: This multi-component implementation study included retrospective and prospective hospital-based screening of patients with premature coronary artery disease (CAD), followed by a geographically targeted community-based screening program linked to a genetically confirmed FH index case in Vietnam. FH was assessed using the Dutch Lipid Clinic Network criteria, with LDL-C thresholds applied for community-level screening. RESULTS: Among patients with premature CAD, phenotypic FH was identified in 2.5% and 8.3% of the retrospective and prospective cohorts, respectively. The higher detection rate in the prospective cohort may reflect more systematic phenotyping. In the community screening, 59.1% of eligible individuals participated, and 10.6% had LDL-C levels ≥ 4.9 mmol/L. CONCLUSIONS: A stepwise targeted FH screening strategy-initiated in clinical populations and extended via geographically targeted community screening-demonstrates feasibility and potential scalability in resource-limited settings and may provide a pragmatic framework for integration into national NCD programs in LMICs. HIGHLIGHTS: - Targeted screening strategies may enhance the detection of FH in resource-limited settings where universal screening is not feasible.- Patients with premature coronary artery disease represent a high FH detection rate.- Geographically targeted community-based screening linked to FH index cases enables identification of individuals with markedly elevated LDL-C levels.- A stepwise approach combining hospital-based and community-based screening may provide a scalable model for FH detection in LMICs.