Background and Purpose-Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Methods-Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genomewide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. Results-Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10-8) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10-7) and ABO (PIS=2.6×10-4), as well as at HDAC9 (PLAS=2.32×10-12), 9p21 (PLAS=3.70×10-6), RAI1-PEMT-RASD1 (PLAS=2.69×10-5), EDNRA (PLAS=7.29×10-4), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10-4). Conclusions-Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.