Objectives: A systematic review and meta-analysis was performed to confirm the relationship between the Klotho single nucleotide polymorphisms (SNPs) and the risk of cardiovascular disease (CVD). Methods: Electronic databases of PubMed, EMBASE, the Cochrane Library and China National Knowledge Infrastructure were searched. Case-control studies or observational studies were included. Data synthesis and analysis were performed using the statistical software STATA. Results: Sixteen studies including 9585 participants provided the valid data for exploring the correlation between the 4 Klotho SNPs and the risk of 3 kinds of CVDs. Overall results showed that the significant correlation was observed between the risk of CVDs and G-395A SNP under the additive genetic models (OR=1.23, 95% CI=1.08-1.40,P=0.001), dominant model (OR=1.24, 95% CI=1.05-1.45, P=0.009) and recessive model (OR=1.61, 95% CI=1.30-2.00, P<0.001). No significant associations were found between the risk of CVDs and C1818T, F352V and C370S SNPs (all P>0.05). Conclusion: This meta-analysis can indicate the G-395A, C1818T SNPs could be a risk factor for coronary heart disease, while the G-395A and F352V SNPs might be a risk for hypertension. No association between the risk of ischemic stroke and the G-395A, F352V and C1818T SNPs could be established from our meta-analysis.