OBJECTIVE Glycated hemoglobin (HbA1c) is positively associated with cardiovascular disease (CVD), although evidence is primarily observational. Mendelian randomization studies have only examined its relation with subtypes of CVD. We examined the relation of HbA1c with CVD and its subtypes in the UK Biobank using Mendelian randomization. RESEARCH DESIGN AND METHODS We used 38 genetic variants strongly and independently related to HbA1c (n = 123,665) applied to the UK Biobank (n = 392,038). We used inverse variance weighting (IVW) to obtain the associations of HbA1c with CVD, coronary artery disease (CAD), and stroke (overall and stroke subtypes). Sensitivity analyses included Mendelian randomization (MR)-Egger, a weighted median, and exclusion of potentially invalid single nucleotide polymorphisms (SNPs). We also applied the same genetic instruments to CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) 1000 Genomes–based genome-wide association study (n = 184,305) as a validation for CAD. RESULTS In the UK Biobank, HbA1c was not associated with CVD using IVW (odds ratio [OR] 1.11 per %, 95% CI 0.83–1.48). However, HbA1c was associated with increased CAD risk (OR 1.50 per %, 95% CI 1.08–2.11) with directionally consistent results from MR-Egger and weighted median. The positive association with CAD was more pronounced when we excluded potentially invalid SNPs (OR 2.24 per %, 95% CI 1.55–3.25). The positive association was replicated in CARDIoGRAM (OR 1.52 per %, 95% CI 1.03–2.26). The association of HbA1c with stroke and its subtypes was less clear given the low number of cases. CONCLUSIONS HbA1c likely causes CAD. The underlying mechanisms remain to be elucidated.