OBJECTIVES: To assess the influence of individual methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase A2756G polymorphisms on the change of serum folate concentration in response to different dosages and durations of folic acid (FA) supplementation in hypertensive Chinese adults. METHODS: A total of 480 patients with mild or moderate essential hypertension were randomly assigned to three treatment groups: (a) enalapril only (10 mg, control group); (b) enalapril FA tablet [10 : 0.4 mg (10 mg of enalapril combined with 0.4 mg of FA), low-FA group]; (c) enalapril FA tablet (10 : 0.8 mg, high-FA group), once daily for 8 weeks. Individual serum folate levels were measured at baseline, and at 4 and 8 weeks posttreatment. RESULTS: After 4 or 8 weeks of treatment, increases in serum folate were seen across all genotypes and FA dosage groups. However, compared with patients with 677CC genotype, those with CT or TT genotype in the low-FA group and TT genotype in the high-FA group still had significantly lower folate concentrations, particularly women. In the low-FA group, patients with CT or TT genotype showed an attenuated response compared with those with CC genotype (median ratio of folate at week 8 to that at baseline: CC,1.953 vs. CT,1.755 or TT,1.637, P<0.01 for both). Such an attenuated response was not observed in the high-FA group. Yet, only in the high-FA group did serum folate appear to reach a plateau after 4 weeks of treatment in all three MTHFR 677 genotypes and the methionine synthase 2756 AG/GG genotype. CONCLUSION: We demonstrated that MTHFR C677T polymorphisms can not only affect serum folate levels at the baseline and post-FA treatment, but also therapeutic responses to various dosages and durations of FA supplementation. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.