<i>Background:</i> African-Americans are likely to develop hypertension and hypertensive nephrosclerosis. This grave prognosis, coupled with familial aggregation of end-stage renal disease (ESRD) in Blacks, prompts a search for genetic risk factors for ESRD. Recent evidence implicates a crucial role for the sympathetic nervous system in progressive renal disease. <i>Methods:</i> We used the African-American Study of Kidney Disease to probe whether β₂-adrenergic receptor (<i>ADRB2)</i> predicts glomerular filtration rate (GFR) decline rate. A total of 580 participants were included. Baseline GFR was 51.2 ± 0.5 ml/min/1.73 m². Subjects were randomized in a 2 × 3 block design: to intensively lowered (MAP ≤92 mm Hg) versus ‘usual’ (MAP = 102–107 mm Hg) blood pressure goal groups, and also divided by three randomized antihypertensive drugs (ramipril, metoprolol, or amlodipine). We scored 4 SNPs at the <i>ADRB2</i> locus. <i>Results:</i> Haplotypes at <i>ADRB2</i> predicted chronic GFR decline rate, GFR declined more slowely in individuals with haplotype-1 (–804G→173T→16Gly→27GIn), and faster in those who carried haplotype-3 (–804G→173T→16Arg→27Gln). <i>ADRB2</i> genotype interacted with antihypertensive drug class to influence GFR slope (p = 0.001–0.037). We extended our findings to an independent case/control sample of Black hypertensive ESRD, in which we found that variant Gly16Arg that tagged the GFR slope-determining <i>ADRB2</i> haplotype also conferred risk for the ESRD trait in Blacks. <i>Conclusions:</i> The GFR decline/progression rate in hypertensive renal disease is controlled in part by genetic variation within the adrenergic pathway.