Objective: Sympathetic nervous system plays a key role in blood pressure control and functional polymorphisms of the beta-2 adrenergic receptor (B2AR) have been implicated in the pathogenesis of hypertension. In particular, functional polymorphism Arg16Gly (46A–>G rs1042713), has been proved to be of clinical relevance. However, limited information is available on its association with baroreflex sensitivity (BRS) and other parameters of autonomic cardiovascular regulation. Aim of our study was to explore this issue. Methods: In the frame of Medellin's Heart Study, a probabilistic sample of 800 subjects from the general population of Medellin (Colombia) was recruited. Individuals with a diastolic blood pressure (DBP)>70th percentile of distribution curve (DBP>85 mmHg), aged 30-65 years and not receiving antihypertensive therapy, were selected (n = 92). Arg16Gly polymorphism was forward and backward genotyped (accuracy >99%), using automated DNA sequencer 3730XL (ABI-Prism). Cardiovascular autonomic modulation was assessed by computer analysis of 10 min beat-to-beat BP and ECG recordings obtained in supine position (Task Force Monitor). BRS was estimated by sequence method as the slope of spontaneous concomitant increases or decreases in systolic (S)BP and RR interval. Low-frequency (LF) and high-frequency (HF) spectral components of heart rate variability (HRV) were assessed by Fourier analysis and expressed in normalized units (nu). LF/HF ratio was also calculated. Results: Allelic distribution of Arg16Gly polymorphism was in Hardy-Weinberg equilibrium. There was highly significant variation in all parameters between Arg/Arg, Arg/Gly and Gly/Gly genotypes. After adjustment for age, sex, smoking, diabetes, SBP and BMI, subjects with Arg/Arg genotype exhibited significantly lower BRS (p < 0.007), higher HRV sympathetic indices (LF; p < 0.003 and LF/HF; p < 0.002) and lower HRV parasympathetic indices (HF; p < 0.003) than those with Gly/Gly genotype. See table. Conclusions: These results indicate that ADRB2 gene may be involved in the modulation of cardiac baroreflex and HRV in humans. In particular, Arginine homozygous genotype of Arg16Gly polymorphism was associated with a decreased BRS and higher indirect indices of sympathetic activity in subjects with high blood pressure.