To assess the association between the elevation of plasma homocysteine (Hcy) level and long-term levodopa (L-dopa) therapy in idiopathic Parkinson's disease (PD). We performed a systematic literature review to recruit original studies published up to May 14, 2012. Studies enrolled should be controlled, with specific information of long-term L-dopa application and plasma Hcy in patients with PD. Effects were summarized using standardized mean differences (SMDs) or weighted mean differences (WMDs). Our search enrolled 22 eligible studies. Plasma Hcy levels were significantly higher in L-dopa-treated patients than those in healthy controls [SMD 0.97; 95% confidence interval (CI) 0.80-1.14, P < 0.001], L-dopa-naive patients with PD (SMD 0.99; 95% CI 0.54-1.44, P < 0.001), and untreated patients (SMD 0.52; 95% CI 0.18-0.86, P < 0.01). However, its levels in untreated patients with PD were not significantly higher than in healthy controls (SMD 0.24; 95% CI -0.03 to 0.51, P > 0.05). Patients with PD treated with L-dopa plus catechol-O-methyltransferase inhibitor (COMT-I) showed lower plasma Hcy concentrations compared with L-dopa-treated patients (WMD 4.62; 95% CI 2.89-6.35, P < 0.001). L-dopa treatment is associated with the increase in plasma Hcy level in patients with PD. COMT-I may attenuate L-dopa-induced elevation of Hcy level.