Rationale: The CysGlyGln haplotype of the 2-adrenergic receptor gene (ADRB2) is functional and associated with altered responses to adrenergic agonists in asthmatic patients. Whether this functional haplotype alters outcome in patients receiving adrenergic agonists in septic shock is unknown. Objectives: To determine whether genetic variation of ADRB2 influences outcome of septic shock. Methods: Two cohorts of septic shock patients were studied: a single center (St. Paul’s Hospital, SPH) cohort (n=589) and the Vasopressin and Septic Shock Trial (VASST) cohort (n=616). The A allele of the rs1042717 G/A polymorphism is in complete linkage disequilibrium with the CysGlyGln haplotype of ADRB2, therefore rs1042717 was genotyped. Modulation by norepinephrine and salbutamol of IL-6 production by stimulated in vitro lymphoblastoid cells was measured by genotype. Measurements and Main Results: Patients who had the AA genotype of rs1042717 displayed increased 28-day mortality in SPH (adjusted hazard ratio 2.23, 95%CI 1.33-3.72, P=0.0022) and this result replicated in VASST (adjusted hazard ratio 2.82, 95%CI 1.56-5.09, P=0.0006). This genotypic effect was eliminated in those patients treated with acute low dose corticosteroids. In all patients the AA genotype was also associated with more organ dysfunction. Patients with the AA genotype had a higher heart rate (SPH, P<0.05; VASST, P<0.05) and required a higher day 1-3 norepinephrine dose (VASST, P<0.05). The AA genotype was associated with decreased norepinephrine and salbutamol inhibition of IL-6 production by stimulated lymphoblastoid cells in vitro (P<0.05). Conclusion: The AA genotype of ADRB2 rs1042717, identifying homozygotes for the CysGlyGln haplotype, was associated with increased mortality and more organ dysfunction in septic shock.