Objective: To evaluate the effect of amantadine on corneal endothelial cells in subjects with Parkinson's disease. Design: Cross-sectional study. Participants: A total of 169 subjects (169 eyes) taking amantadine orally for Parkinson's disease and the same number of age- and gender-matched controls. Methods: Endothelial indices were compared between the amantadine-treated and age-matched control groups. The amantadine-treated group was divided into 3 subgroups according to the cumulative dose and duration of treatment. Endothelial changes were compared between the amantadine group and the normal control group, and among subgroups. Main Outcome Measures: Slit-lamp biomicroscopy, central corneal thickness (CCT), endothelial cell density (ECD), coefficient of variation, and hexagonality. Results: The amantadine group had significantly lower ECD (mean ± standard error; 2662.47±29.06 vs. 2784.72±25.89, P = 0.002), lower hexagonality (56.94±1.07 vs. 60.97±0.87, P = 0.004), and greater coefficient of variation (35.59±0.57 vs. 32.66±0.52, P = 0.000) compared with the age-matched control group. Longer duration and higher cumulative dose amantadine therapy led to a greater reduction in ECD (P<0.05) compared with the normal age-matched control group. Conclusions: Amantadine is more likely to have an effect on corneal endothelial cells in a dose-dependent manner when used long-term. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.