BACKGROUND Exercise performance in patients with congestive heart failure is partially dependent on cardiac beta1-adrenergic receptor (beta1AR) function. There are 2 common polymorphisms of the beta1AR gene that alter the encoded amino acids at positions 49 (Ser or Gly) and 389 (Gly or Arg) and alter receptor function in vitro. Their relevance to modification of cardiac function in heart failure is not known. METHODS Exercise testing was performed in 263 patients with idiopathic or ischemic cardiomyopathy (left ventricular ejection fraction approximately 25%). Potential associations were sought between beta1AR genotypes and the primary outcome variables of peak oxygen consumption (VO2), heart rate response, and exercise time. RESULTS The major determinants of exercise capacity were the polymorphisms at position 389, where patients homozygous for Gly389 had significantly lower peak VO2 compared with those with Arg389 (14.5 +/- 0.6 vs 17.7 +/- 0.4 mL/kg/min, P =.006), despite similar clinical characteristics including left ventricular ejection fraction. Consistent with a gene dose-response, heterozygosity was associated with an intermediate response (16.9 +/- 0.6 mL/kg/min, P <.05). When position 49 genotypes were included, a graded relationship between the 5 2-locus haplotypes and VO2 was found. Two haplotypes displayed the most divergent peak VO2: homozygous Gly389/Ser49, and homozygous Arg389/Gly49 carriers (14.4 +/- 0.5 vs 18.2 +/- 0.8 mL/kg/min, P =.001). Genotype did not predict the heart rate response. The above results were independent of beta-blocker or other medication use, left ventricular ejection fraction, beta2AR genotype, or other demographic and clinical characteristics. CONCLUSIONS beta1AR polymorphisms are a significant determinant of exercise capacity in patients with congestive heart failure. Early identification, by genetic testing for these polymorphisms, of heart failure patients at risk for development of depressed exercise capacity may be useful for initiation of specific therapy tailored to genotype.