Background: Sialorrhea, the excessive flow of saliva from the mouth, causes distress in about half of patients with amyotrophic lateral sclerosis (ALS). Treatments of sialorrhea in ALS include systemic anticholinergic drugs, amitriptyline, botulinum toxin injection, and salivary gland radiotherapy, although each has limitations. Scopolamine transdermal patches have been used to prevent motion sickness since the 1980s but have also been used to treat sialorrhea in oropharyngeal disease, cerebral palsy, and Parkinson’s disease. To date, no blinded, controlled studies of sialorrhea in ALS have been reported. Methods: A crossover, double-blind comparative study was conducted by randomly assigning patients to receive scopolamine or placebo patches for 1 week. Results: A total of 10 patients (three males and seven females; mean age 71.6 years) were enrolled. The mean volume of daily oral suction was decreased with scopolamine treatment. However, there were no significant differences between scopolamine and placebo in terms of a visual analogue scale of sialorrhea severity and difficulty, and the saliva item of the ALS Functional Rating Scale-Revised (ALSFRS-R). Conclusions: Our findings suggest that scopolamine patches might decrease saliva production and relieve sialorrhea in some patients with ALS. However, these findings were not statistically significant for all patients.