End-stage renal disease (ESRD) due to hypertension is common and displays familial aggregation in African Americans, suggesting genetic risk factors, including adrenergic activity alterations which are noted in both hypertension and ESRD. We analysed 554 hypertensive nephrosclerosis participants (without clinically significant proteinuria) from the longitudinal National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) African American Study of Kidney Disease and Hypertension (AASK) cohort to determine whether decline in glomerular filtration rate (GFR) over approximately 3.8 years was predicted by common genetic variation within the adrenergic beta-1 (ADRB1) receptor at non-synonymous positions Ser49Gly and Arg389Gly. The polymorphism at Ser49Gly (though not Arg389Gly, in only partial linkage disequilibrium at r(2) = 0.18) predicted the chronic rate of GFR decline, with minimal decline in Gly(49)/Gly(49) (minor allele) homozygotes compared to Ser(49) carriers; concordant results were observed for haplotypes and diploid haplotype pairs at the locus. An independent replication study in 1244 subjects from the San Diego Veterans Affairs Hypertension Cohort confirmed that Gly(49)/Gly(49) homozygotes displayed the least rapid decline of eGFR over approximately 3.6 years. We conclude that GFR decline rate in hypertensive renal disease is controlled in part by genetic variation within the adrenergic pathway, particularly at ADRB1. The results suggest novel strategies to approach the role of the adrenergic system in the risk and treatment of progressive renal disease.