Hypertension is a known risk factor for renal cell carcinoma (RCC), although the underlying biological mechanisms of its action are unknown. To clarify the role of hypertension in RCC, we examined the risk of RCC in relation to 142 single-nucleotide polymorphisms (SNPs) in eight genes having a role in blood pressure control. We analyzed 777 incident and histologically confirmed RCC cases and 1035 controls who completed an in-person interview as part of a multi-center, hospital-based case-control study in Central Europe. Genotyping was conducted with an Illumina GoldenGate Oligo Pool All assay using germ line DNA. Of the eight genes examined, AGT (angiotensinogen) was most strongly associated with RCC (minimum P-value permutation test = 0.02). Of the 17 AGT tagging SNPs considered, associations were strongest for rs1326889 [odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.15-1.58] and rs2493137 (OR = 1.31, 95% CI = 1.12-1.54), which are located in the promoter. Stratified analysis revealed that the effects of the AGT SNPs were statistically significant in participants with hypertension or high body mass index (BMI) (> or =25 kg/m(2)), but not in subjects without hypertension and with a normal BMI (<25 kg/m(2)). Also, haplotypes with risk-conferring alleles of markers located in the promoter and intron 1 regions of AGT were significantly associated with RCC compared with the common haplotype in subjects with hypertension or high BMI (global P = 0.003). Our findings suggest that common genetic variants of AGT, particularly those in the promoter, increase RCC risk among subjects who are hypertensive or overweight.