In this study, we investigated the effects of selegiline on levodopa treatment and parkinsonian disability over several years of treatment in patients with early Parkinson's disease (PD). The 163 patients were randomized to receive either selegiline or placebo in addition to levodopa in a double-blind, parallel-group study design, and the patients were to be followed up until a defined termination point or for 5 years. All patients had previously either never (two thirds) or for <6 months (one third) received levodopa. After 1 year of treatment or at withdrawal from study or both, the patients were divided according to specified diagnostic criteria into groups of definite, probable, possible, or unlikely PD. The efficacy parameters were levodopa therapy, Unified Parkinson's Disease Rating Scale (UPDRS) with subscales, and the time to develop wearing-off fluctuations or reaching the termination point. Evaluation of efficacy was performed for all patients with PD and for patients with a definite and probable disease. The results of this study are based on an interim analysis when 80% of the 163 randomized patients had been followed up for ≥3 years. Nine patients were excluded from the study because of protocol violations or because the patients were diagnosed as unlikely PD. At the time of interim analysis, 39 patients had been withdrawn from the study because of adverse effects or their own wish. Eighteen patients had reached the termination point, and 97 patients (observation time, 30–54 months) were still in the study. Among the patients receiving selegiline, we found a rather stable daily levodopa dose during 54 months of therapy, compared with an anticipated increase among patients with levodopa monotherapy. Concurrently, patients in the selegiline group showed a trend to develop less severe parkinsonian disability and a lower frequency of motor fluctuations and need for additional antiparkinsonian medication. The results of this study indicate that early combination therapy of selegiline and levodopa compared with levodopa monotherapy has an increasingly favorable impact on the long-term daily levodopa dose and may possibly delay the development of disability in PD.