Essential hypertension (EH) accounts for 90-95% of hypertension cases. EH, as a progressive cardiovascular syndrome arising from complex and interrelated etiologies, results from combined and interactive effects of genetic and environmental factors. The objective was to investigate the ACE I/D and GNB3 C825T polymorphisms and both genotypes combined with seeking gene-gene interactions to further clarify the role of these genes in the pathogenesis of EH. Eight hundred and ten consecutive ethnic-matched unrelated north Indian subjects, 360 healthy controls from the general population and 450 patients, were enrolled. Plasma renin activity and plasma aldosterone concentration were measured. The variant GNB3 C825T was typed by SNaPshot and analyzed on Genetic Analyzer and GeneScan. Genotypes-combinations and gene-gene interactions were also performed. We found that the plasma ACE levels were higher in hypertensive patients than healthy controls. The ACE DD genotype was associated with the highest circulating ACE levels, ID heterozygotes were associated with intermediate and II heterozygotes with the lowest ACE levels in either patients or controls. Our data suggested a significant interaction between the GNB3 825T allele and the ACE D allele in CVD and likely EH. The patients bearing (DD+CT or ID+TT) and (DD+TT) combinations, respectively, showed a significant association with EH. Logistic regression revealed a 2.7-fold greater risk of hypertension associated with the (DD+CT or ID+TT) combination, and likewise, a 6.4-fold greater chance of hypertension was associated with the (DD+TT) combination. GNB3 C825T and ACE I/D gene-gene interaction in our study revealed that (DD+CT or ID+TT) and (DD+TT) combinations were significantly associated with EH and higher risk of hypertension, respectively. In a synergistic gene-to-gene interaction among the three polymorphisms, genotypic combinations containing three and/or four unfavorable alleles had a significantly increased chance of EH. These results strengthen the hypothesis that genotypic combinations are more important than a single gene polymorphism.