Levodopa treatment improves significantly not only the parkinsonian disability but also the mortality rate. However, during long-term levodopa treatment the therapeutic benefit gradually declines. Furthermore, most cognitive skills improve initially, but long-term levodopa treatment is associated with declining intellectual capacity and dementia. In patients on long-term levodopa treatment there seems to be a low threshold for certain clinical side-effects, especially postural hypotension, psychiatric disturbances and various types of fluctuations in disability. Low age at onset of Parkinson's disease, and at the commencement of levodopa therapy, the duration of levodopa treatment and a high dose of levodopa seem to be significant risk factors for the development of response fluctuations, but not the pretreatment duration of Parkinson's disease nor the disability of the patients. A readjustment of the levodopa dosage, and as an adjuvant drug treatment, deprenyl, a specific inhibitor of MAO type B, or a direct-acting dopamine agonist may prove helpful in the management of fluctuations in disability. It is important, moreover, to try to prevent these phenomena by taking into account the predictive risk factors of response fluctuations in the treatment strategy of Parkinson's disease.