BackgroundStroke is a common cerebrovascular disease. The purpose of this study was to explore the association betweenLIPCsingle nucleotide polymorphisms (SNPs) and the risk of stroke in the Chinese population.MethodsThis study recruited 710 stroke patients and 701 healthy controls. The four SNPs (rs690, rs6083, rs3829461, and rs6074) inLIPCwere genotyped by the Agena MassARRAY. The correlation betweenLIPCpolymorphisms and stroke risk was measured by odds ratio (OR) and 95% confidence interval (CI). In addition, multifactor dimensionality reduction (MDR) analysis was used to evaluate the impact of SNP–SNP interaction on stroke risk.ResultsOverall analysis showed that rs690 was associated with an increased risk of stroke (T vs. G: OR = 1.19, 95% CI: 1.01–1.40,p= 0.041; additive: OR = 1.20, 95% CI: 1.01–1.42,p= 0.036). The stratified analysis revealed that rs690 was associated with an increased risk of stroke in subjects aged ≤ 64 years, male patients, and smokers, and rs6074 was associated with an increased risk of stroke in subjects aged > 64 years, male patients, drinkers, and non-smokers (p< 0.05). The results of the MDR analysis suggested the four-locus model as the most favorable model for assessing the risk of stroke. The analysis of clinical parameters of stroke patients showed that rs690 was correlated with platelet distribution width (PDW) (p= 0.014) and hematocrit levels (p= 0.004), and rs6074 was correlated with low-density lipoprotein cholesterol (LDL-C) level (p= 0.033). Furthermore, bioinformatics analysis results demonstrated that the expression levels ofLIPCand its related genes (APOB, CETP, PNPLA2, andLMF1) were significantly different between the control and stroke groups (p< 0.05), andLIPC-related proteins were mainly related to lipid metabolism.ConclusionThis study indicated that rs690 and rs6074 inLIPCwere significantly associated with increased risk of stroke in the Chinese population, possibly by regulating the levels of PDW, HCT, and LDL-C.