BACKGROUND AND PURPOSE: Elevated C-reactive protein (CRP) is associated with an increased risk of ischemic stroke (IS). However, the causality of this association is uncertain. We aim to investigate whether genetically raised plasma CRP concentration levels are associated with the IS based on the Mendelian randomization (MR) method. METHODS: Based on the National Center for Biotechnology Information SNP database, the Chinese online genetic database as well as previously published studies, four CRP-associated SNPs alleles (rs1130864, rs1205, rs876537 and rs3093059) with minor allele frequency (MAF) ≥ 0.15 were selected and the concentration levels of CRP were measured in 378 first-ever IS patients and 613 healthy controls. RESULTS: Three SNPs were chosen and used as instrumental variables. The adjusted odds ratios (ORs) (95% confidence interval (95% CI)) of IS per addition of the modelled allele were 1.07 (0.79-1.45) for rs876537, 0.99 (0.73-1.35) for rs1205 and 1.08 (0.71-1.65) for rs3093059. The OR (95% CI) of IS for the plasma CRP ≥ 2.0 mg/L was 2.19 (1.06-4.53) as compared with < 2.0 mg/L. The adjusted OR (95% CI) of IS per genetically predicted 10% higher CRP concentration, based on the three SNPs as the instruments, was 1.02 (0.94-1.11). Furthermore, the similar results were obtained with the adjusted ORs (95% CI) of 1.00 (0.88-1.13) and 1.04 (0.93-1.16), respectively, for large-artery atherosclerosis and small-artery occlusion per genetically predicted 10% higher CRP concentration. CONCLUSIONS: This MR study provides no clear support that elevated CRP concentration is causally associated with the risk of IS.