Background: Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. Objectives: The aim of this study was to identify genetic factors associated with ACE inhibitor–associated angioedema. Methods: A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors ≤180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model. Results: The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor–treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor–treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 × 10^–8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 × 10⁻⁹). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 × 10⁻³). We found that carriers of the risk allele had significantly lower systolic (−0.46 mm Hg per T allele; 95% CI: −0.83 to −0.10; P = 0.013) and diastolic (−0.26 mm Hg per T allele; 95% CI: −0.46 to −0.05; P = 0.013) blood pressure. Conclusions: In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B₂ gene were associated with increased risk for ACE inhibitor–related angioedema.