Hypertension tends to perpetuate in families and the heritability of hypertension is estimated to be around 20–60%. So far, the main proportion of this heritability has not been found by single-locus genome-wide association studies. Therefore, the current study explored gene-gene interactions that have the potential to partially fill in the missing heritability. A two-stage discovery-confirmatory analysis was carried out in the Framingham Heart Study cohorts. The first stage was an exhaustive pairwise search performed in 2320 early-onset hypertensive cases with matched normotensive controls from the offspring cohort. Then, identified gene-gene interactions were assessed in an independent set of 694 subjects from the original cohort. Four unique gene-gene interactions were found to be related to hypertension. Three detected genes were recognized by previous studies, and the other 5 loci/genes (MAN1A1, LMO3, NPAP1/SNRPN, DNAL4, and RNA5SP455/KRT8P5) were novel findings, which had no strong main effect on hypertension and could not be easily identified by single-locus genome-wide studies. Also, by including the identified gene-gene interactions, more variance was explained in hypertension. Overall, our study provides evidence that the genome-wide gene-gene interaction analysis has the possibility to identify new susceptibility genes, which can provide more insights into the genetic background of blood pressure regulation.