Background Earlier, a G/T single nucleotide polymorphism (SNP) in the HMGCR gene was shown to significantly reduce the overall serum lipids response to pravastatin. This study aimed to investigate the relationship of the rs17238540 SNP with coronary heart disease, stroke and cardiovascular disease risk. Design Cross-sectional study from the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort. Methods Genotype was determined by pyrosequencing 23 011 participants, for whom clinical and biochemical data were available. Baseline risk factors according to genotype were evaluated, and the risk for fatal and nonfatal stroke, ischaemic heart disease and all types of cardiovascular diseases were assessed by logistic regression after approximately 11 years of follow-up. Results The G allele carriers presented 1.4 mmHg higher systolic blood pressure and 0.8 mmHg higher diastolic blood pressure than those who were TT carriers. They also presented higher risk of prevalent total (odds ratio: 1.44, 95% confidence interval: 1.05–1.97, P = 0.025) and nonfatal (odds ratio: 1.56, 95% confidence interval: 1.12–2.17, P = 0.009) stroke events compared with the TT individuals in the multivariate models. Conclusion An association between the rs17238540 SNP and stroke risk was observed, independent of the effect of the SNP on the blood pressure. The possible mechanisms involved, besides the effect on blood pressure, might be related to pleiotropic functions of the HMGCR, and remain to be explored.