Abstract Dopa decarboxylase (DDC) is a candidate biomarker in Parkinson’s disease (PD), but its levels are influenced by dopamine replacement therapy (DRT), complicating interpretation. We used high-throughput proteomics to analyze serum and CSF samples from PD patients, individuals with idiopathic REM-sleep behaviour disorder, and controls to assess DRT effects. In serum, DDC increased and prolactin and AOC3 decreased with higher levodopa equivalent daily doses, showing drug class-specific associations. Longitudinally, serum DDC and prolactin levels changed with DRT, while AOC3 remained stable. In CSF, DDC was elevated regardless of treatment, while prolactin was reduced only in treated PD. These results indicate that serum changes in DDC, prolactin, and AOC3 primarily reflect treatment exposure rather than disease biology. Our findings highlight the need to account for medication effects in proteomic studies, identify AOC3 as a novel DRT-sensitive protein, and support the potential of treatment-responsive proteins as pharmacodynamic markers in PD.