Clozapine is the only evidence-based antipsychotic for treatment-resistant schizophrenia. However, it has considerable side effects, limiting its usability and reducing patients' adherence. One of the most common and distressing side effects is hypersalivation, which can be debilitating, stigmatizing and potentially dangerous through its association with aspiration pneumonia. There is a paucity of evidence guiding possible treatment strategies for hypersalivation. This study aims to examine the efficacy of hyoscine (scopolamine) for clozapine-induced hypersalivation. Fourteen inpatients diagnosed with treatment-resistant schizophrenia, treated with clozapine and suffering from hypersalivation were randomized to receive hyoscine 0.3 mg and placebo daily for 4 weeks each in a randomized, double-blind, placebo-controlled cross-over trial. The primary outcome was improvement in the Toronto Nocturnal Hypersalivation Scale. The secondary outcomes were change in the mass of the pillowcase, anxiety, depression and quality of life. Hypersalivation improved significantly with hyoscine over placebo when measured by the Toronto Nocturnal Hypersalivation Scale (odds ratio=0.21, 95% confidence interval: 0.16-0.28, P<0.001). No significant difference was observed in any of the secondary outcomes. This study showed a beneficial effect of hyoscine over placebo for clozapine-induced hypersalivation.