Abstract—The ₂-adrenoceptor agonist clonidine reduces blood pressure more effectively in White than Black Americans despite similar degrees of sympatholysis. Functional genetic variation in receptor signaling mechanisms, for example in the 3 G-protein subunit (GNB3 C825T) and in the _2C-adrenoceptor subtype (ADRA2C del322–325), may affect drug responses. We examined the hypothesis that there are ethnic differences in the responses to the highly selective ₂-agonist, dexmedetomidine, and that these genetic variants contribute to interindividual variability in drug responses. In a placebo-controlled, single-masked study, 73 healthy subjects (37 whites and 36 blacks) received 3 placebo infusions and then 3 incremental doses of dexmedetomidine (cumulative dose, 0.4 µg/kg), each separated by 30 minutes. Blood pressure, heart rate, and plasma catecholamine concentrations were determined after each infusion. We measured dexmedetomidine concentrations after the last infusion and determined ADRA2C del322–325 and GNB3 C825T genotypes. Dexmedetomidine lowered blood pressure and plasma catecholamine concentrations significantly (all P<0.001). There was substantial interindividual variability in the reduction of systolic blood pressure (range, 1 to 34 mm Hg) and plasma norepinephrine concentrations (range, 24 to 424 pg/mL). However, there were no differences between black and white subjects in dexmedetomidine responses (P>0.16 for all outcomes) before or after adjustment for covariates. Neither ADRA2C del322–325 nor GNB3 C825T genotypes affected the responses to dexmedetomidine (all P>0.66). There is large interindividual variability in response to the selective ₂-AR agonist dexmedetomidine, and neither ethnicity nor ADRA2C and GNB3 genotypes contribute to it. Further studies to identify determinants of ₂-AR–mediated responses will be of interest.