The present study was undertaken to determine whether combined treatment with prokinetic trimebutine and mosapride has a synergic effect on gastrointestinal motility and visceral pain associated with gastrointestinal dysfunction. To develop effective gastroprokinetic agents with greater potencies than trimebutine or mosapride for the treatment of gastrointestinal tract disease, a mixture of trimebutine and mosapride was designed and prepared. In the present study, treatment with trimebutine alone showed a dose-dependent effect on propelling movements of normal small and large intestine in mice, whereas mosapride effected only small intestine motility. Co-administration of trimebutine with mosapride, a well-established prokinetic drug, produced a synergistic influence on normal small intestine motility, but demonstrated an unclear effect on large intestine motility, with a slight tendency to reduce the propelling time. In a stress model, the small and large intestine motilities were significantly decreased. The reduction of intestine motility was restored to a normal level and the restoring effect was more pronounced in the combined treatment with trimebutine plus mosapride than treatment with trimebutine or mosapride alone. Furthermore, treatment with trimebutine plus mosapride significantly decreased acute visceral pain which was not controlled by trimebutine or mosapride alone. These data suggest that combination therapy with trimebutine plus mosapride has a synergic effect on small and large intestine motility and visceral pain control in gastrointestinal disorders.