BACKGROUND Studies on genes of endothelial and vascular homeostasis are inadequate in females. METHODS We investigated the role of 7 variants of ACE, AGT and NOS3 and their correlation with NO(x) levels and ACE activity in hypertension susceptibility in 910 case-controls of both genders. RESULTS Prevalence of alleles D of ACE I/D; -6A of AGT -6G/A; -786C, 894T and 4a of NOS3 -786T/C, 894G/T and 4b/4a polymorphisms was observed in patients (P< or =0.05). The 3 genotypes-combinations containing 6+5 wild-type alleles of AGT and NOS3 were significantly less prevalent in patients (P< or =0.0003). The haplotypes 235T/174T/-6A of AGT (P=4E-3) and -786T/894G/4a and -786C/894G/4a of NOS3 (P=2E-3, P=0.011, respectively) were significantly more prevalent in patients. The AGT and NOS3 findings were similar in males. Genotypes-combinations with 6+5 wild-type alleles of AGT correlated with higher NO(x) levels (P=0.03). The NOS3 genotypes-combinations having 6 and 6+5 wild-type alleles correlated with decreased ACE activity (P=0.025, P=0.0015, respectively) and increased NO(x) levels (P=0.001, P=0.0001, respectively) in patients. In gene-gene interactions, ACE D allele associated with < or =4 wild-type alleles containing genotypes-combinations of AGT and NOS3 in patients (P< or =0.04). CONCLUSION Within gene and between genes interactions of variants influence ACE activity and NO(x) levels and associate with EH.