Dopamine via G-protein-coupled receptor kinase 4 (GRK-4) regulates sodium (Na) balance in the proximal tubule of the kidney. Single-nucleotide polymorphisms of GRK-4 have been linked to impaired natriuresis and salt-sensitive hypertension. The purpose of this report was to determine the effect of GRK-4 gene polymorphisms on the blood pressure (BP) responses to dietary intervention. Black subjects aged 50-75 years with mild-to-moderate hypertension were randomised to an 8-week dietary intervention (n = 40) or standard diet (n = 40). BP was measured at baseline and at 8 weeks using 24-h ambulatory BP. All subjects underwent DNA analysis for the R65L and A142V polymorphisms. Data were analysed using generalised linear models. For the whole group, between-diet differences in mean 24-h ambulatory systolic BP was -4.53 mm Hg (95% confidence interval -9.05 to -0.01, P = 0.05). In the intervention arm, the combined CC and CT group of the A142V showed a significant reduction in both systolic and diastolic ambulatory BP (-10 mm Hg, P = 0.023 and -6.5 mm Hg, P= 0.01, respectively), whereas the TT group demonstrated no reduction. Similarly, the combined GG and GT groups of the R65L showed a significant reduction in ambulatory BP (-10.6 mm Hg for systolic, P = 0.004 and 5.8 mm Hg for diastolic, P= 0.006). There was no response in the TT group. GRK-4 polymorphisms predict BP response to dietary modification in Black subjects with mild-to-moderate hypertension. These data may provide at least one among a range of clinical tools to target selected hypertensives to dietary intervention.