Objective To investigate the influence of organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1) and apolipoprotein E (ApoE) gene polymorphisms on clopidogrel response in very high-risk atherosclerotic cardiovascular disease (ASCVD) patients.Methods We enrolled 183 very high-risk ASCVD patients treated with clopidogrel at our hospital from January 2023 to January 2024. Patients were stratified into resistant (n = 51) and sensitive (n = 132) groups based on clopidogrel response. SLCO1B1 and ApoE genotypes were determined, and their associations with clinical parameters were analyzed.Results The clopidogrel resistance rate was 27.87% (51/183). The resistant group showed significantly higher cholesterol levels (P < 0.05), leukocyte counts (P < 0.05), and diabetes prevalence (P < 0.05) compared to the sensitive group. Genetic analysis revealed higher frequencies of SLCO1B1 1a/1b and 1b/1b genotypes in resistant patients (both P < 0.05); Lowered 15 and increased 1b allele frequencies in resistant group (both P < 0.05); Greater prevalence of ApoE e3/e4 and e4/e4 genotypes in resistant patients (both P < 0.05); Higher e4 allele frequency in resistant group (P < 0.05).Conclusion Both SLCO1B1 and ApoE polymorphisms significantly associate with clopidogrel resistance in ASCVD patients, suggesting potential pharmacogenetic markers for antiplatelet therapy optimization.