The potential difference in the concentration-effect relationship of oral sequential doses of levodopa was explored in six Parkinsonian patients with complex fluctuating response. These patients showed “wearing-off phenomena” characterized by a transient worsening of motor function at the end of the first morning dose response to below baseline values and complained of a progressive reduction of levodopa effect during the day. A first standard levodopa dose was given in the morning, after an overnight fast and levodopa withdrawal. A second equal levodopa dose was administered immediately at the end of the first dose deterioration phase. Postimprovement worsening of motor response was also observed after the second levodopa dose in all patients. No significant difference in the pharmacokinetics of levodopa or in duration or magnitude of motor response could be appreciated between the two doses. These results further support the suggestion that, under controlled dietary conditions, plasma levodopa levels and effects relationship is reproducible between doses. Moreover, even when transient deterioration of motor function occurs between levodopa doses, the central dopaminergic system appears to remain responsive to the drug.