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To evaluate the contributions of environmental and genetic cues to renal sodium handling in a population-based study.Our study subjects were suspected hypertensive patients being off antihypertensive medication for at least 2 weeks and referred to our hypertension clinic for 24-hour ambulatory blood pressure monitoring. We collected serum and 24-hour urine for measurement of sodium, creatinine and lithium concentration. Sodium and creatinine concentrations were measured by coupled plasma mass spectrometry. Fractional excretion of lithium (FELi) and fractional distal reabsorption rate of sodium (FDRNa) were calculated as markers of proximal and distal sodium handling, respectively. We used the ABI SNapShot method and genotyped 12 SNPs from candidate genes (ADD1, ADD2, ADD3, LSS, ABCB1, HSD3B1, NEDD4L, AGTR1 and WNK1) and 6 SNPs (rs10502933, rs2345088, rs12513375, rs16817782, rsOur study included 1409 untreated patients and 664 men (mean age, 51.0 years). In adjusted analysis, FELi was positively associated with age but negatively with the ratio of the total cholesterol and high density lipid (P ≤ 0.003). FDRNa was negatively with current smoking and waist circumference. After adjusting the host and environmental factors and after Bonferroni correction, among the 18 genetic variations, only AGTR1 rs2131127 was significantly associated with FELi (P = 0.032). In AGTR1 rs2131127 CC homozygotes (n = 162) had lower daytime systolic blood pressure than T allele carriers (131.4 vs. 133.6 mmHg, P = 0.04). Season and humidity together explained ∼1.3% and ∼3.5% of the variation of the fractional excretion of lithium and distal reabsorption of sodium, respectively, while genetic cues just 1.10% or less.Environmental compared with genetic cues are critical drivers of renal sodium handling.