Background Novel therapies are needed for the treatment of motion sickness given the inadequate relief, and bothersome and dangerous adverse effects of currently approved therapies. Neurokinin-1 (NK1) receptor antagonists have the potential to be effective in improving the symptoms of motion sickness, given the involvement of Substance P in nauseogenic and emetic pathways and the expression of NK1 receptors in the gastrointestinal system. Here, we evaluated the efficacy of tradipitant, a novel NK1 receptor antagonist, in preventing motion sickness in variable sea conditions. Methods A total of 126 adults participated in the Motion Sifnos Study. Groups of participants were assigned to one of seven boat trips lasting approximately four hours on the Pacific Ocean. Participants were randomized 1:1 to tradipitant 170 mg or placebo and completed the Motion Sickness Severity Scale (MSSS) every 30 minutes, in addition to other assessments. Severity of motion sickness was assessed with the incidence of vomiting and the MSSS. Results Participants on tradipitant had a significantly lower incidence of vomiting as compared to those on placebo across all boat trips (tradipitant=17.5%, placebo=39.7%, p=0.0039). For trips exposed to rough sea conditions, the difference in the incidence of vomiting between the groups was more dramatic (tradipitant=15.79%, placebo=72.22%, p=0.0009). Across these trips, motion sickness symptoms were significantly lower in the tradipitant group compared to the placebo group (tradipitant=3.19, placebo=4.57, p=0.0235). Discussion Tradipitant has the potential to be an effective therapy for the prevention of vomiting and treatment of nausea in people with motion sickness.