In humans, subjects homozygous for arginine (ArgArg) at codon16 of the β2-adrenergic receptor (β2AR) have been shown to have greater agonist-mediated desensitization than subjects homozygous for glycine (GlyGly). We sought to determine if this substitution differentially influenced cardiovascular function during short duration (9 min) low and high intensity exercise (40 and 75% of peak work). Healthy Caucasian ArgArg (n = 16), GlyGly (n = 31) and ArgGly (n = 17) subjects matched for age, sex and peak oxygen uptake were studied. There were no differences in adrenaline (ADR) at rest or with heavy exercise, but the ArgArg group had lower ADR with light exercise (P = 0.04). Resting heart rate (HR) was higher in ArgArg (P < 0.01), while cardiac output (Q̇), stroke volume (SV), and mean arterial pressure (MAP) were lower than the other groups (HR=86 ± 2, 78 ± 2, 80 ± 1 beats min-1; Q̇ = 5.7 ± 0.81, 6.1 ± 0.18, 6.7 ± 0.22 l min-1; SV = 68 ± 3, 82 ± 3, 89 ± 4ml beat-1; MAP = 92 ± 1, 103 ± 2, 98 ± 1 mmHg - for ArgArg, ArgGly and GlyGly, respectively, means ± S.E.M., P < 0.01), however, no differences were observed in systemic vascular resistance (SVR). With low intensity exercise and high intensity exercise the ArgArg group continued to have a lower Q̇, SV and MAP compared to the other groups (P < 0.05),with no differences observed in SVR. During recovery, the ArgArg subjects continued to have a lower MAP but there were no differences in HR, Q̇, or SVR. These data suggest that subjects homozygous for Arg at codon 16 of the β2AR have reduced Q̇ and MAP at rest that persist during exercise with no evidence for differential changes over the course of exercise despite large changes in catecholamines. This may suggest possible genotype-related differences in baseline receptor function or density which causes phenotypic differences at rest that are sustained during short-term exercise.