Methylenetetrahydrofolate Reductase (MTHFR) C677T gene polymorphism is associated with decreased MTHFR enzyme activity that leads to hyperhomocysteinemia and hypertension. The MTHFR C677T polymorphism is also associated with lower affinity and faster unbinding of flavin adenine dinucleotide, a riboflavin-derived cofactor for MTHFR enzyme. Natuna is a district which once reported has the highest prevalence of hypertension in Indonesia, based on a national basic health research. Therefore, this study aims to investigate the association between MTHFR C677T polymorphism and riboflavin intake with hypertension in the Natuna district population. An analytic cross-sectional population study was conducted in the region. Data of demographic, physical examination, and food recall, as well as MTHFR genotyping from blood samples of study subjects were collected. The subjects were 268 adults, among which 128 (45.9%) had hypertension, 49 (17.5%) had mutant allele of MTHFR genotype (CT or TT), and 158 (56.4%) had low daily riboflavin intake. There was association between MTHFR C677T polymorphism and hypertension [OR 3.387 (1.724 – 6.654), p = 0.001]. Post-hoc analysis showed that group of mutant MTHFR C677T genotype with low riboflavin intake showed strong association with hypertension [OR 19.320 (4.498–82.980), p<0.01]. Meanwhile, group with mutant MTHFR C677T genotype and normal riboflavin intake did not show a significant association with hypertension. As a conclusion, there was association between interaction of riboflavin intake and MTHFR C677T polymorphism with hypertension. This suggests possibility of riboflavin supplementation in population with high prevalence of hypertension especially those with MTHFR C677T gene polymorphism