The beta2/beta1 adrenoceptor ratio increases in congestive heart failure (CHF), making the heart relatively more dependent on inotropic, lusitropic, and chronotropic stimulation by the beta2-adrenergic receptor (ADRB2). In healthy human beings, those who are homozygous for arginine (Arg) at amino acid 16 of the ADRB2 have reduced receptor function when compared with individuals homozygous for glycine (Gly) at this position. The cardiovascular effects of the Arg16Gly polymorphism of the ADRB2 in CHF are not well understood. The aim of this study was to examine the influence of common polymorphisms of the ADRB2 on cardiovascular structure and function in patients with CHF. Echocardiography, neurohormonal assays, and exercise tests were performed in 68 healthy individuals and 95 patients with CHF. All of the patients with CHF were stable, New York Heart Association class II to III, of ischemic or nonischemic cause, with an ejection fraction of 40% or less. Of the patients with CHF, 16 were Arg/Arg, 36 were Arg/Gly, and 43 were Gly/Gly at amino acid 16. In those without CHF, the Arg16Gly polymorphism of the ADRB2 had no effect on cardiovascular function. In contrast, in CHF, Arg/Arg homozygotes had higher plasma norepinephrine and atrial natriuretic peptide levels, greater left atrial diastolic dimension, higher peak velocity of early/late diastolic filling ratio, and shorter deceleration time compared with Gly16 homozygotes. Furthermore, Arg16 homozygotes had reduced exercise tolerance compared with Gly16 homozygotes (evidenced by shorter exercise duration and lower peak oxygen consumption per unit time), and a lesser chronotropic response to exercise. In patients with CHF, but not in demographically matched healthy persons, the Arg16Gly polymorphism of the ADRB2 exerts important effects on cardiovascular structure and function, neurohormonal activation, and exercise tolerance.