In recent years, L-Dopa treatment has been indicated as an acquired cause of hyperhomocysteinemia (HHcy). The mechanism underlying L-Dopa-related HHcy is the O-methylation of the drug catalyzed by the enzyme catechol-O-methyltransferase (COMT). Folate and cobalamin status also influences the effects of L-Dopa on plasma homocysteine (Hcy) levels. Although clinical correlations of HHcy in Parkinson's disease still remain uncertain, management of elevated plasma Hcy levels has been advocated, due to multiple cytotoxic effects of Hcy on neurons. This review summarizes data available in the literature concerning the two main therapeutic approaches to L-Dopa-related HHcy (use of COMT inhibitors or B vitamins diet supplementation).