Fenofibrate is among the drugs of choice for treatment of hypertriglyceridaemia and low levels of high-density lipoprotein (HDL)-cholesterol, both recognised as risk factors for cardiovascular disease. Recently, a number of studies have shown an elevation of homocysteine levels with fenofibrate or bezafibrate therapy. Homocysteine is an atherogenic amino acid derived from the methionine cycle. At present, the underlying mechanism for this elevation has not been elucidated. While deterioration of vitamin status does not seem to be involved, impairment of renal function or changes in creatine metabolism are regarded as probable mechanisms. In patients not receiving lipid-lowering drugs, vitamin supplementation with folic acid and vitamin B12 effectively reduces the plasma homocysteine level. Two studies have shown that addition of folic acid or a vitamin combination to fenofibrate prevented most of the homocysteine increase associated with fenofibrate. Although the consequence of increasing homocysteine levels for cardiovascular risk has not been proven at present, it has to be considered that fenofibrate will be given for long-term treatment. Therefore, addition of folic acid and vitamin B12 to fenofibrate can be recommended to prevent the increase of homocysteine associated with fenofibrate, or treatment could be changed to gemfibrozil, which does not increase plasma homocysteine levels.