BACKGROUND: Parkinson's disease (PD) is the most common movement disorder among adults, affecting 2% of the world population older than 65 years of age. No diagnostic biomarker for routine use in clinical settings currently exists. Dysregulation of microRNAs (miRNAs) has been implicated in various neurodegenerative conditions, including PD. Distinct miRNAs have been demonstrated to be involved in the regulation of α-synuclein, a key player in PD pathogenesis; miR-153 and miR-223 are downregulated in the brain and serum of parkinsonian GFAP.HMOX1 transgenic mice where they directly regulate α-synuclein. OBJECTIVE: To ascertain whether salivary miR-153 and miR-223 are similarly downmodulated in, and may serve as diagnostic biomarkers of, idiopathic PD. METHODS: Using reverse transcriptase quantitative polymerase chain reaction, miR-153 and miR-223 levels were evaluated in the saliva of 77 non-neurological controls and 83 PD patients. Levels of heme oxygenase-1 and α-synuclein were measured using enzyme-linked immunosorbent assay. Analyses were adjusted by age, sex, medication exposure, disease duration, and relevant comorbidities. RESULTS: Log-transformed expression levels of miR-153 and miR-223 were significantly decreased in the saliva of human PD patients in comparison with nonneurological controls. The miRNA expression levels did not change as a function of disease progression (Hoehn and Yahr staging). The area under the receiver operating characteristic curve separating controls from PD patients was 79% (95% confidence interval, 61%-96%) for miR-153 and 77% (95% confidence interval, 59%-95%) for miR-223. The ratios of miRNAs to oligomeric α-synuclein, total α-synuclein, or heme oxygenase-1 protein did not improve accuracy of the test. CONCLUSION: Salivary miR-153 and miR-223 levels may serve as useful, noninvasive, and relatively inexpensive diagnostic biomarkers of idiopathic PD. © 2019 International Parkinson and Movement Disorder Society.