BACKGROUND: Levodopa combined with carbidopa and entacapone (LCE) and levodopa combined with benserazide (LB) are commonly used treatment options in every stage of Parkinson's disease. Although both combinations aim to enhance dopamine bioavailability and improve motor symptoms, their short-term biochemical effects remain to be clarified. This study aims to compare the short-term effects of LCE and LB on plasma dopamine levels in patients with early-stage, unilateral Parkinson's disease. METHODS: This prospective, single-center, randomized controlled study included patients diagnosed with early-stage Parkinson's disease presenting with unilateral motor symptoms. Participants were randomly assigned to receive either LCE or LB therapy. This study was a randomized controlled trial performed according to the Consolidated Standards of Reporting Trials (CONSORT). Venous blood samples were collected before drug administration and at 90- and 180-minute post-administration to measure plasma dopamine levels using high-performance liquid chromatography. RESULTS: Ninety patients were included in the study. Of these, 34.4% were female, and the median age was 69.5 years. The tremor-dominant subtype was observed in 92.2% of patients. LCE was administered to 48.9% of the patients, while 51.1% received LB. Both LCE and LB led to increases in plasma dopamine concentrations within the first 180 minutes. However, no significant difference was observed between the 2 treatment groups and within groups over time, in terms of dopamine elevation (P > .05, all values). CONCLUSION: In this study, no significant difference was observed in the short-term effects of LCE and LB combinations on plasma dopamine levels in patients with early-stage Parkinson's disease with unilateral involvement. Further large-scale, multicenter studies with extended follow-up are required to assess long-term clinical outcomes, including motor response duration and adverse effects.