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The purpose was to examine the effect of intervention with riboflavin (a cofactor for MTHFR) on blood pressure in patients homozygous (TT genotype) for the common 677C→T polymorphism in MTHFR.We investigated 197 premature cardiovascular disease patients, prescreened for the MTHFR 677C→T polymorphism, from an original cohort of 404 to select those with the TT genotype (n = 60) and a similar number with heterozygous (CT; n = 85) or wild-type (CC; n = 75) genotypes. Of these, 181 completed an intervention in which participants were randomized within each genotype group to receive 1.6 mg per day riboflavin or placebo for 16 weeks.Among patients taking one or more antihypertensive drugs at recruitment (82%), we observed that target blood pressure (<140/90 mmHg) had been achieved in only 37% patients with the TT genotype compared with 59% with the CT and 64% with the CC genotype (P < 0.001). Riboflavin intervention reduced mean blood pressure specifically in those with the TT genotype (from 144/87 to 131/80 mmHg; P < 0.05 systolic; P < 0.05 diastolic), with no response observed in the other genotype groups.Riboflavin is effective in reducing blood pressure specifically in patients with the MTHFR 677 TT genotype. The findings, if confirmed, may have important implications for the prevention and treatment of hypertension.