Cardiovascular disease (CVD) is the primary cause of death in Korea. Hyperhomocysteinemia confers an independent risk for CVD comparable to the risk of smoking and hyperlipidemia. The purpose of this study was to assess the effect of cardiovascular risk factors and body composition change on homocysteine (Hcy) levels in Korean men and women. The association between body composition and Hcy levels was investigated in a 2-yr prospective cohort study of 2,590 Koreans (mean age 45.5±9.6 yr). There were 293 cases of hyperhomocysteinemia (>14 µM/L) at follow-up. Increases in total body fat proportion and decreases in lean body mass (LBM) were significantly associated with increases in Hcy concentration after controlling for confounding factors. Further adjustments for behavioral factors showed that decreases in LBM were associated with Hcy increase. Decrease in LBM also predicted hyperhomocysteinemia at follow-up, after controlling for confounding factors. There was no significant association between change in body mass index (BMI) and Hcy concentrations over time. Hcy changes over time were related to change in LBM and body fat content, whereas BMI or weight change did not predict change in Hcy levels. Changes in ratio of LBM to total fat mass may contribute to hyperhomocysteinemia.