Opicapone (Ongentys®), a potent, oral, third-generation, long-acting, peripheral catechol-O-methyltransferase (COMT) inhibitor, is approved as the adjunctive treatment to levodopa (L-Dopa)/dopa-decarboxylase inhibitor (DDCI) therapy in adults with Parkinson's disease (PD) and end-of-dose motor fluctuations who cannot be stabilized on those combinations. Opicapone is a hydrophilic 1,2,4-oxadiazole analog with a pyridine N-oxide at position 3, with these modifications enhancing its potency and extending its duration of action, whilst avoiding cell toxicity. In preclinical animal studies, Opicapone-induced inhibition of peripheral (but not central) COMT activity was associated with a prolonged increase in systemic and central exposure to L-Dopa, with a corresponding reduction in 3-OMD exposure. Following single or multiple doses of Opicapone (5–1200 mg) in healthy adult volunteers or patients with PD, Opicapone inhibited COMT activity in ex vivo erythrocyte assays in a reversible dose-dependent manner, with the duration of Opicapone-induced COMT inhibition independent of dose. Adjunctive Opicapone was generally well tolerated during more than a year of treatment in BIPARK I and BIPARK II (double-blind plus extension phases). The recommended dosage is 50 mg once daily, which should be taken at bedtime at least 1 h before or after L-Dopa combinations.