['The genes FTO and GNB3 are implicated in essential hypertension but their interaction remains to be explored. This study investigates the role of interaction between the two genes in the pathophysiology of essential hypertension.', 'In a case-control study comprising 750 controls and 550 patients, interaction between the polymorphisms of FTO and GNB3 was examined using multifactor dimensionality reduction (MDR). The influence of interaction on clinical phenotypes like systolic and diastolic blood pressure, mean arterial pressure and body mass index was also investigated. The 3-locus MDR model comprising FTO rs8050136C/A and GNB3 rs1129649T/C and rs5443C/T emerged as the best disease conferring model. Moreover, the interacted-genotypes having either 1, 2, 3, 4 or 5 risk alleles correlated with linearly increasing odds ratios of 1.91 (P\u200a=\u200a0.027); 3.93 (P\u200a=\u200a2.08E-06); 4.51 (P\u200a=\u200a7.63E-07); 7.44 (P\u200a=\u200a3.66E-08) and 11.57 (P\u200a=\u200a1.18E-05), respectively, when compared with interacted-genotypes devoid of risk alleles. Furthermore, interactions among haplotypes of FTO (H1-9) and GNB3 (Ha-d) differed by >1.5-fold for protective-haplotypes, CTGGC+TC [H2+Ha] and CTGAC+TC [H4+Ha] (OR\u200a=\u200a0.39, P\u200a=\u200a0.003; OR\u200a=\u200a0.22, P\u200a=\u200a6.86E-05, respectively) and risk-haplotypes, AAAGC+CT [H3+Hc] and AAAGC+TT [H3+Hd] (OR\u200a=\u200a2.91, P\u200a=\u200a9.98E-06; OR\u200a=\u200a2.50, P\u200a=\u200a0.004, respectively) compared to individual haplotypes. Moreover, the effectiveness of gene-gene interaction was further corroborated with a 1.29-, 1.25- and 1.38-fold higher SBP, MAP and BMI, respectively, in patients having risk interacted-haplotype H3+Hc and 2.48-fold higher SBP having risk interacted-haplotype H3+Hd compared to individual haplotypes.'] Do interactions between the FTO and GNB3 genes contribute to varied clinical phenotypes in hypertension?