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Objective: The objective of this study was to investigate the effect of selegiline first as monotherapy and then in combination with levodopa in the early phase of PD., Methods: A total of 157 de novo PD patients were randomized to receive either selegiline or placebo in a double-blind study until levodopa therapy became necessary. Thereafter, the drugs were withdrawn for an 8-week washout period to evaluate the possible symptomatic effect of selegiline., Results: Analysis of Kaplan-Meier survival curves for each group showed that selegiline delayed significantly the need for levodopa therapy (p = 0.028). The semiannual rate of disability progression was slowed down significantly in the selegiline group analyzed with the Unified Parkinson's Disease Rating Scale (total and motor scores; p < 0.001). Selegiline had a "wash-in" effect (i.e., an initial symptomatic amelioration of PD at 6 weeks and 3 months). However, after the 8-week washout period, no significant differences in the deterioration of disability between the groups was revealed in any of the scales, suggesting that besides having a slight symptomatic effect, selegiline may also have neuroprotective effects. Similarly, the progression of symptoms from baseline to the end of the washout period was significantly slower (p = 0.033) in the selegiline group when the progression was adjusted by the time to reach the end point. Selegiline was well tolerated., Conclusions: Selegiline delayed significantly the need to start levodopa in early PD. After a 2-month washout period (before the start of levodopa therapy) no significant symptomatic effect of selegiline was seen in comparison with the placebo group, supporting the concept of neuroprotective properties of the drug.