Pharmacological management of Parkinson’s disease (PD) is complex and may negatively impact patients' adherence to therapy. Several objective and subjective approaches are used to assess therapeutic adherence. Measurement of biological markers, that are well correlated with the effect of the medications, and that are distributed into easily accessible body fluids would be feasible approach for measuring therapeutic adherence for these medications. S100B protein has been proposed to be involved in the pathophysiology of PD. The study aims to measure the serum S100B level in PD patients and to assess its potentials to be used as a biomarker to predict therapeutic adherence in PD patients. Sixty-eight adult outpatients, of both genders, who were already diagnosed with PD, receiving different anti-Parkinson medications, were enrolled in this cross-sectional study. Hoehn and Yahr scale was used to determine the stage of disease; while, therapeutic adherence to treatment was assessed using the Arabic version of Morisky Medication Adherence Scale (MMAS-8). Serum S100B level was measured by enzyme-linked immune sorbent assay. Serum S100B level of participants was 10.55 (13.3) ng/l, and there was no significant difference between medians of S100B protein according to disease stages, P =0.975. Serum S100B level in patients with poor therapeutic adherence [14.2 (13.2) ng/l] was significantly higher than that in patients with good therapeutic adherence [3.14 (3.34)]; P = 0.008. Furthermore, serum S100B level with the MMAS-8; (r= -0.414, P = 0.001). Finally, at a cut-off point 3.57 ng/l and above, serum S100B level was shown to have good potential [area under the curve (AUC)= 0.715], as biomarker of therapeutic adherence with 70.6% sensitivity and 70.6%, specificity; P = 0.008. In conclusion, serum S100B level in PD patients is negatively correlated with therapeutic adherence level and has good potentials as biomarker of therapeutic adherence in PD patients to anti-Parkinson medications.