Context: Severe hypoglycemic events are unevenly distributed in people with type 1 diabetes, making a genetic influence probable. Of the common adrenoceptor b-2 receptor gene (ADRB2) polymorphisms, the Arg16 allele is associated with receptor downregulation and reduced agonist-mediated endogenous glucose production. Objective: We tested the hypothesis that the Arg16 variant is associated with severe hypoglycemia. Method: A cohort of 311 patients with type 1 diabetes reported severe hypoglycemic events retrospectively in a validated questionnaire. The patients were characterized by diabetes history, state of hypoglycemia awareness, C-peptide status, HbA1c, and ADRB2 genotype. Results: The ADRB2 Gly16Arg genotype distribution was in Hardy-Weinberg equilibrium. The rate of severe hypoglycemia differed among all genotypes (P = 0.01). Patients homozygous for the Arg16 genotype (AA; n = 60) had a relative rate (RR) of severe hypoglycemia of 2.2 (95% CI, 1.3 to 3.6) compared with patients homozygous for the Gly16 genotype (GG; n = 116; P = 0.002). Among patients with impaired awareness or unawareness (n = 175), those with the AA genotype (n = 33) had an RR of severe hypoglycemia of 3.2 (95% CI, 1.7 to 6.0) compared with patients with the GG genotype (n = 58; P, 0.000). Genotype was not associated with state of hypoglycemia awareness per se, as assessed by any of three classification methods. The difference was not explained by other risk factors. Conclusion: Genetic polymorphism in ADRB2 is associated with risk of severe hypoglycemia in individuals with type 1 diabetes, especially in those with impaired hypoglycemia awareness.