Prospective studies have reported that circulating cholesterol abnormalities are predictive of hypertension. As a test of the causal influence of circulating cholesterols on hypertension, we used a meta-based Mendelian randomization analysis to determine whether the apolipoprotein E (ApoE) gene polymorphism epsilon 2/epsilon 3/epsilon 4 related to cholesterol changes is associated with hypertension. Data were available from 17 study populations, encompassing 2896 hypertensive patients and 2898 controls. A random effects model was applied irrespective of a between-study heterogeneity, and publication bias was examined using a funnel plot and Egger's test. An overall comparison of the ApoE gene alleles epsilon 4 with epsilon 3 yielded a significant 81% increased risk for hypertension (95% confidence interval (95% CI): 1.41-2.32; P<0.0005). Restricting the analysis to populations of Asian descent resulted in a 1.87-times higher likelihood of developing hypertension (95% CI: 1.41-2.32; P<0.0005). Compared with epsilon 3 carriers, epsilon 4 allele carriers had significantly higher levels of total cholesterol (standardized mean difference (SMD)=0.39; 95% CI: 0.2-0.57; P<0.0005) and low-density lipoprotein cholesterol (SMD=0.43; 95% CI: 0.23-0.64; P<0.0005). The predicted odds ratio (OR) for a 1 mmol l(-1) increase in total cholesterol was 4.58 (95% CI: 1.83-67.21) when all qualified studies were included and 4.98 (95% CI: 1.94-76.36) for Asian-descent populations. Similarly, the predicted OR for a 1-mmol l(-1) increase of low-density lipoprotein cholesterol was 3.97 (95% CI: 1.71-43.48) in all populations and 4.29 (95% CI: 1.81-43.38) in Asian-descent populations. Taken together, our findings suggest a casual influence of high circulating total cholesterol and low-density lipoprotein cholesterol levels on the development of hypertension. Hypertension Research (2012) 35, 434-440; doi: 10.1038/hr.2011.202; published online 24 November 2011