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Background and Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of LDL-C leading to premature cardiovascular disease (CAD). Only about 40% of individuals with a clinical diagnosis of FH have a causative genetic variant identified, and a proportion of genetically negative cases may have a polygenic cause rather than a still unidentified monogenic cause. This work aims to evaluate and validate the role of a polygenic risk score (PRS) associated with hypercholesterolemia in a Brazilian FH cohort and its clinical implications., Methods: We analyzed a previously derived PRS of 12 and 6 SNPs (Single Nucleotide Polymorphism) in 684 FH individuals (491 mutation-negative [FH/M-], 193 mutation-positive [FH/M+]) and in 1605 controls. Coronary artery calcium (CAC) score was also evaluated., Results: The PRS was independently associated with LDL-C in control individuals ( p  < 0.001). Within this group, in individuals in the highest quartile of the 12 SNPs PRS, the odds ratio for CAC score >100 was 1.7 (95% CI: 1.01-2.88, p  = 0.04) after adjustment for age and sex. Subjects in the FH/M- group had the highest mean score in both 12 and 6 SNPs PRS (38.25 and 27.82, respectively) when compared to the other two groups ( p  = 2.2 × 10-16). Both scores were also higher in the FH/M+ group (36.48 and 26.26, respectively) when compared to the control group (p < 0.001 for the two scores) but inferior to the FH/M- group. Within FH individuals, the presence of a higher PRS score was not associated with LDL-C levels or with CAD risk., Conclusion: A higher PRS is associated with significantly higher levels of LDL-C and it is independently associated with higher CAC in the Brazilian general population. A polygenic cause can explain a fraction of FH/M- individuals but does not appear to be a modulator of the clinical phenotype among FH individuals, regardless of mutation status., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RDS has received honoraria related to consulting, research and or speaker activities from: Abbott, Amgen, Aché, Astra Zeneca, Esperion, EMS, GETZ Pharma, Kowa, Libbs, Merck, MSD, Novo-Nordisk, Novartis, PTC Therapeutics, Pfizer, Roche and Sanofi. IRL has received a scholarship from Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil (CAPES) #88887.531079/2020-00. RDS is recipient of a scholarship from Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico, Brazil (CNPq) #303734/2018-3. The ELSA-Brasil baseline study was supported by the 10.13039/501100006506Brazilian Ministry of Health (Science and Technology Department) and the BrazilianMinistry of Science and Technology (10.13039/501100004809Financiadora de Estudos e Projetos and 10.13039/501100003593CNPq 10.13039/100013101National Research Council)., (© 2022 The Authors.)