Black patients may be less responsive to beta-blockers than whites. Genetic variants in the beta1-adrenergic receptor (beta1-AR) associated with lesser response to beta-blockers are more common in blacks than in whites. The purpose of this study was to determine whether ethnic differences in response to beta-blockade can be explained by differing distributions of functional genetic variants in the beta1-AR.We measured sensitivity to beta-blockade by the attenuation of exercise-induced tachycardia in 165 patients (92 whites), who performed a graded bicycle exercise test before and 2.5 h after oral atenolol (25 mg). We determined heart rate at rest and at three exercise levels from continuous ECG recordings and calculated the area under the curve. We also measured plasma atenolol concentrations and determined genotypes for variants of the beta1-AR (Ser49Gly, Arg389Gly) and alpha2C-AR (del322-325). The effects of ethnicity, genotype, and other covariates on the heart rate reduction after atenolol were estimated in multiple regression analyses.Atenolol resulted in a greater reduction in exercise heart rate in whites than in blacks (P=0.006). beta1-AR Arg389 (P=0.003), but not the alpha2C-AR 322-325 insertion allele (P=0.31), was independently associated with a greater reduction in heart rate area under the curve. Ethnic differences in sensitivity to atenolol remained significant (P=0.006) after adjustment for beta1-AR and alpha2C-AR genotypes.Ethnic differences in sensitivity to the beta1-blocker atenolol persist even after accounting for different distributions of functional genetic beta1-AR variants, suggesting that additional, as yet unidentified factors contribute to such ethnic differences.