OBJECTIVE To investigate the effect of enalapril on plasma homocysteine (Hcy) levels and the association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with the changes of Hcy levels in response to enalapril among patients with essential hypertension. METHODS A total of 130 patients with mild-to-moderate essential hypertension were enrolled and enalapril was orally administered at a dose of 10 mg/d for eight weeks. Plasma Hcy levels were measured by denaturing high-performance liquid chromatography (DHPLC) at baseline and after eight weeks of treatment. Genotyping of MTHFR C677T polymorphism was performed by TaqMan probe technique. RESULTS Compared with baseline, plasma Hcy levels did not change significantly after eight weeks (P=0.81). Stratified by baseline Hcy levels, a significant increase in plasma Hcy levels (P=0.02) among those with Hcy <10 micromol/L was observed, in contrast to no significant changes in plasma Hcy levels (P=0.54) among those with Hcy > or =10 micromol/L. No significant association was observed between MTHFR C677T polymorphism and changes in Hcy levels in response to enalapril. CONCLUSIONS Enalapril may cause an increase in plasma Hcy levels among the hypertensives with low baseline Hcy levels. There was no significant association between MTHFR C677T genotypes and changes in Hcy levels in response to enalapril among subjects with essential hypertension.