The serpin family A member 1 (SERPINA1) Z allele is present in approximately one in 25 individuals of European ancestry. Z allele homozygosity (Pi*ZZ) is the most common cause of alpha 1‐antitrypsin deficiency and is a proven risk factor for cirrhosis. We examined whether heterozygous Z allele (Pi*Z) carriers in United Kingdom (UK) Biobank, a population‐based cohort, are at increased risk of liver disease. We replicated findings in Massachusetts General Brigham Biobank, a hospital‐based cohort. We also examined variants associated with liver disease and assessed for gene–gene and gene–environment interactions. In UK Biobank, we identified 1,493 cases of cirrhosis, 12,603 Z allele heterozygotes, and 129 Z allele homozygotes among 312,671 unrelated white British participants. Heterozygous carriage of the Z allele was associated with cirrhosis compared to noncarriage (odds ratio [OR], 1.53; P = 1.1×10−04); homozygosity of the Z allele also increased the risk of cirrhosis (OR, 11.8; P = 1.8 × 10−09). The OR for cirrhosis of the Z allele was comparable to that of well‐established genetic variants, including patatin‐like phospholipase domain containing 3 (PNPLA3) I148M (OR, 1.48; P = 1.1 × 10−22) and transmembrane 6 superfamily member 2 (TM6SF2) E167K (OR, 1.34; P = 2.6 × 10−06). In heterozygotes compared to noncarriers, the Z allele was associated with higher alanine aminotransferase (ALT; P = = 4.6 × 10−46), aspartate aminotransferase (AST; P = 2.2 × 10−27), alkaline phosphatase (P = 3.3 × 10−43), gamma‐glutamyltransferase (P = 1.2 × 10−05), and total bilirubin (P = 6.4 × 10−06); Z allele homozygotes had even greater elevations in liver biochemistries. Body mass index (BMI) amplified the association of the Z allele for ALT (P interaction = 0.021) and AST (P interaction = 0.0040), suggesting a gene–environment interaction. Finally, we demonstrated genetic interactions between variants in PNPLA3, TM6SF2, and hydroxysteroid 17‐beta dehydrogenase 13 (HSD17B13); there was no evidence of epistasis between the Z allele and these variants. Conclusion: SERPINA1 Z allele heterozygosity is an important risk factor for liver disease; this risk is amplified by increasing BMI.