Background -Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death(SCD), mediated in part by the β2-adrenergic receptor(B2AR). We investigated whether variation in the B2AR gene is associated with SCD risk. Methods and Results -In this study, 4441 white and 808 black Cardiovascular Health Study(CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study(CABS). In CHS, Gly 16 and Gln27 allele frequencies were 62.4%and 57.1%among white and 50.1%and 81.4%among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk(P=0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers(ethnicity-adjusted hazard ratio[HR], 1.56; 95%confidence interval[CI], 1.17 to 2.09; P=0.003). The increased risk did not differ significantly between white(HR, 1.62; 95%CI, 1.18 to 2.23) and black(HR, 1.23; 95%CI, 0.61 to 2.48) participants, although the confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had higher SCD risk than Glu27 carriers(odds ratio, 1.64; 95%CI, 1.02 to 2.63; P=0.040). Gly16Arg was not associated with SCD risk in either study. Conclusions -Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those at increased SCD risk. Background-Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death (SCD), mediated in part by the β2-adrenergic receptor (B2AR). We investigated either variation in the B2AR gene is associated with SCD risk. Methods and Results-In this study, 4441 white and 808 black Cardiovascular Health Study (CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study (CABS). In CHS, Gly 16 and Gln27 allele frequencies were 62.4% and 57.1% among white and 50.1% and 81.4% among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk (P = 0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers (e (HR, 1.62; 95% CI, 1.18 to 2.23). The increased risk did not differ significantly from white (HR, 1.56; 95% confidence interval [CI], 1.17 to 2.09; In the CABS replication study, Gln27 homozygous participants similarly had a higher SCD risk than Glu27 carriers (odds ratio, 1.64; 95 (CI) 0.61 to 2.48) % CI, 1.02 to 2.63; P = 0.040). Gly16Arg was not associated with SCD risk in either study. Conclusions-Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in Study of genetic variation within the B2AR gene may help identify those at increased SCD risk.