Background: The α₁-antitrypsin Z (rs28929474) allele may lead to alterations in hemostasis either through liver disease or effects on coagulation factors. Objectives: To test the hypothesis that the α₁-antitrypsin Z genetic variant is associated with increased risk of venous thromboembolism. Methods: A total of 107 075 individuals from the Copenhagen General Population Study were used to test the association of the α₁-antitrypsin Z genetic variant with risk of venous thromboembolism, including deep venous thrombosis and pulmonary embolism, prospectively. Confirmatory analyses were done in the UK Biobank. Results: During follow-up, venous thromboembolism was diagnosed 6649 times in noncarriers, 436 times in heterozygotes, and 10 times in homozygotes. Hazard ratios for venous thromboembolism in α₁-antitrypsin Z heterozygotes and homozygotes versus noncarriers were 1.1 (95% confidence interval, 1.0–1.2) and 2.2 (1.3–3.7). A one Z allele increase was associated with a hazard ratio for venous thromboembolism of 1.2 (1.0–1.3). The corresponding odds ratio in the UK Biobank was 1.2 (1.1–1.3). The absolute risk of venous thromboembolism associated with α₁-antitrypsin ZZ homozygosity was 7.8% (3.6–12.1). The corresponding estimates were 20.1% (9.1–31.2) for prothrombin G20210A and 15.0% (12.6–17.4) for factor V Leiden. The fraction of venous thromboembolic events attributable to the α₁-antitrypsin Z allele was 0.7% (0.1–1.3). For the prothrombin G20210A and factor V Leiden mutations, population attributable fractions were 1.2% (0.9–1.6) and 10.5% (9.9–11.1). Conclusion: In conclusion, α₁-antitrypsin ZZ homozygosity was associated with a 2.2-fold risk of venous thromboembolism and had a comparable population attributable fraction to prothrombin G20210A.