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Clozapine-induced sialorrhea (CIS) is a common, treatment-limiting, and stigmatizing side effect. All systemic agents that are used for CIS may increase clozapine side effects such as blood pressure changes, constipation, or arrhythmias or may have a negative impact on cognition. Sublingual application of antimuscarinic medications might be a low side effect option for treatment of CIS. Our aim is to propose an off-label treatment option of tropicamide ophthalmic solution given orally via sublingual route for CIS and stimulate further examination. A 33-year-old male inpatient with schizophrenia had been on clozapine 800 mg and amisulpride 600 mg per day. His drooling was occasional and severe as drool dripped off his chin during the day and night. Tropicamide 1% (1 mg/ml) ophthalmic solution was applied orally via sublingual route 1–2 drops at each side of his mouth before going to bed as monotherapy for CIS. Wet area over the pillow, Visual Analogue Scale (VAS), Nocturnal Hypersalivation Rating Scale, the MOS 36-Item Short-Form Health Survey (SF-36), Udvalg for Kliniske Undersøgelser Side Effect Rating Scale, the Scale for the Assessment of Negative Symptoms, and the Scale for the Assessment of Positive Symptoms were administered at baseline visit and at one-week intervals. No side effects were observed. On VAS, the patient rated his sialorrhea 5/7 at baseline, 4/7 after one 1 drop, and 3/7 after 2 drops. Nocturnal hypersalivation yielded score 4 before tropicamide was initiated. After 1 drop of tropicamide at each side of the mouth, the score was 3 and after 2 drops at each side, it was 2. Tropicamide ophthalmic solution might present as a low side effect, off-label option for treatment of CIS. The promising effect should be examined by randomized controlled trials to translate this into clinical practice.