BackgroundTo investigate the association ofHMGCRandNPC1L1gene polymorphisms with residual cholesterol risk (RCR) in patients with premature triple-vessel disease (PTVD).MethodsThree SNPs withinHMGCRincluding rs12916, rs2303151, and rs4629571, and four SNPs withinNPC1L1including rs11763759, rs4720470, rs2072183, and rs2073547 were genotyped. RCR was defined as achieved low-density lipoprotein cholesterol (LDL-C) concentrations after statins higher than 1.8 mmol/L (70 mg/dL).ResultsFinally, a total of 609 PTVD patients treated with moderate-intensity statins were included who were divided into two groups: non-RCR group (n = 88) and RCR group (n = 521) according to LDL-C concentrations. Multivariate logistic regression showed the homozygotes for the minor allele of rs12916 withinHMGCRgene (CC) were associated with a 2.08 times higher risk of RCR in recessive model [odds ratio (OR): 2.08, 95% confidence interval (CI): 1.16–3.75]. In codominant model, the individuals homozygous for the minor allele of rs12916 (CC) were associated with a 2.26 times higher risk of RCR (OR: 2.26, 95% CI: 1.16–4.43) while the heterozygous individuals (CT) were not, compared with the individuals homozygous for the major allele of rs12916 (TT). There was no significant association between the SNPs withinNPC1L1gene and RCR in various models.ConclusionsWe first reported that the variant homozygousCCof rs12916 withinHMGCRgene may incur a significantly higher risk of RCR in PTVD patients treated with statins, providing new insights into early individualized guidance of precise lipid-lowering treatment.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12872-023-03285-w.