The objective of this study was to investigate the risk factors of wearing-off phenomenon in Parkinson's disease (PD) and propose safe dosage of levodopa to reduce wearing-off development based on Chinese cohort. Patients with PD who had taken levodopa (l-dopa) for at least 1 month were recruited. Wearing-off was diagnosed based on validated Chinese version of a patient self-rated 9-question Wearing-Off Questionnaire (WOQ-9) and clinical definition. Eleven variables (gender, disease duration at l-dopa initiation, disease duration at assessment, age at onset, age at assessment, H-Y stage, UPDRS III, l-dopa daily total dosage and dosage adjusted to weight, duration of l-dopa treatment, initial drug recipe) were included in our analysis. Univariate analysis, multivariate logistic regression analysis and decision tree classification model(DTC) were used to detect risk factors of wearing-off. Receiver operating characteristic (ROC) curve and DTC were used to investigate cut-off value of l-dopa to best predict wearing-off. Two hundred and thirty-four patients were investigated in our study, among whom 111 developed wearing-off. Patients with wearing-off tended to receive higher l-dopa dosage and endure longer duration of l-dopa treatment. l-Dopa dosage as 281 mg/day and 4.2 mg/kg/day by ROC, as well as 269 mg/day and 3.2 mg/kg/day by DTC were cut-off values for wearing-off. l-Dopa dosage and duration of l-dopa treatment were related to increased wearing-off development. Cumulative l-dopa dosage and l-dopa daily dosage were better predictive of wearing-off. Inadequate evidence was present for delayed l-dopa initiation. l-Dopa daily dosage no more than 275 mg or 4.2 mg/kg was regarded as safe.