<jats:p> <jats:bold> <jats:italic>Background—</jats:italic> </jats:bold> Elevated circulating levels of fetuin-A in blood have been associated with increased risk of cardiovascular disease. The goal of our study was to prospectively investigate the potential causal nature of the association between fetuin-A levels and myocardial infarction (MI) and ischemic stroke by applying a Mendelian randomization approach. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> Five tagging single-nucleotide polymorphisms (rs2248690, rs2070633, rs2070635, rs4917, and rs6787344) capturing the common genetic variation of the fetuin-A coding gene α <jats:sub>2</jats:sub> -Heremans-Schmid glycoprotein ( <jats:italic>AHSG</jats:italic> ) were genotyped in a case-cohort comprising 214 MI cases, 154 ischemic stroke cases, and 2152 persons who remained free of cardiovascular disease events in the European Prospective Investigation into Cancer and Nutrition-Potsdam study. One single-nucleotide polymorphism (rs6787344) was discarded because of Hardy-Weinberg disequilibrium. All <jats:italic>AHSG</jats:italic> tagging single-nucleotide polymorphisms were associated with fetuin-A plasma levels ( <jats:italic>P</jats:italic> <0.0001). <jats:italic>AHSG</jats:italic> rs4917 C>T showed the strongest association, explaining 21.2% of the phenotypic variance independent of potential confounding factors (+35.5 μg/mL increase per C-allele, <jats:italic>P</jats:italic> =2�10 <jats:sup>−121</jats:sup> ). Furthermore, the rs4917 C-allele showed a significant association with MI (adjusted hazard rate ratio [RR] 1.34, 95% CI 1.05 to 1.70, <jats:italic>P</jats:italic> =0.02). Based on this association, the expected RR for MI corresponding to 1 SD in fetuin-A was 1.54 and, thus, strikingly matches the previously observed association between fetuin-A plasma levels and MI risk (RR 1.59). </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusions—</jats:italic> </jats:bold> These data provide evidence for the causal nature of the recently reported association between fetuin-A plasma levels and MI risk, thereby suggesting an involvement of fetuin-A in the pathogenesis of cardiovascular disease. </jats:p>