Levodopa application improves motor symptoms in patients with Parkinson disease (PD). Levodopa induces lower cortisol plasma levels and decreases serotonergic activity in certain brain areas of fish. The objectives of this study were to perform repeat cortisol concentration measurements before and after the administration of soluble levodopa/benserazide (dose, 200 mg) in 32 patients with PD during an interval of 150 minutes. The cortisol concentrations significantly decreased after levodopa intake, particularly in the patients with more advanced stage of PD, but not in the less affected patients. There were significantly lower cortisol levels in the patients at the advanced stage of PD compared with those of the earlier patients with PD, particularly at −30, 0, and 90 minutes before/after levodopa application. Significant inverse relations were found between the cortisol levels and the Unified Parkinson Disease Rating Scale total score, particularly at 60 and 90 minutes after levodopa intake. Neurodegeneration occurs in striatal regions and in the brain stem of patients with PD. The 5-HT-containing neuronal terminals of the brain stem hypothetically mediate the cortisol level decrease after levodopa intake because these cells contain an important fraction of amino acid decarboxylase. Therefore, this compartment may be the site of enzymatic conversion of superfluous, exogenous levodopa to dopamine. Consequently, short-term levodopa administration also leads to levodopa uptake in these 5-HT-metabolizing neurons, which interferes with the 5-HT synthesis and may cause a decrease of 5-HT levels. These lower 5-HT levels reduce the hypothalamic function and, via the corticotropin axis, the subsequent peripheral cortisol release. Thus, levodopa-induced cortisol decrease may be related to PD progression.