Elevated C-reactive protein (CRP) is associated with an increased risk of ischaemic stroke (IS). However, the causality of this association is uncertain. The aim is to investigate whether genetically raised plasma CRP concentration levels are associated with IS on the basis of the Mendelian randomization method. Based on the National Center for Biotechnology Information single nucleotide polymorphism (SNP) database, the Chinese online genetic database as well as previously published studies, four CRP-associated SNP alleles (rs1130864, rs1205, rs876537 and rs3093059) with minor allele frequency ≥0.15 were selected and the concentration levels of CRP were measured in 378 first-ever IS patients and 613 healthy controls. 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 plasma CRP ≥2.0 mg/l was 2.19 (1.06-4.53) 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, similar results were obtained with 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. This Mendelian randomization study provides no clear support that elevated CRP concentration is causally associated with the risk of IS. © 2019 European Academy of Neurology.