In 18 patients with Parkinson's disease, the effects of pergolide after 28 months of treatment were compared with the response after the initial 10-week therapy. At a mean 3.2-mg daily dose of pergolide, the daily dose of levodopa was still 33% lower than at the onset of pergolide therapy. The mean motor disability score, which decreased by 65% during the first 10 weeks of pergolide, was still decreased by 42% after 28 months. In the 12 patients with on-off effect, the percent time on increased 117% during the first phase of the study and was still increased 63% after more than 2 years of pergolide therapy. Sudden freezing episodes became the most disabling problem in the majority of patients. "Down-regulation" of dopamine receptors may contribute, but it is not the only cause of loss of responsiveness to pergolide.