We investigated whether the prokinetic activity of mosapride, a 5-hydroxytryptamine 4 receptor agonist, in combination with proton pump inhibitor (PPI) would ameliorate symptoms of gastroesophageal reflux disease (GERD) in Japanese patients. Patients who experienced reflux symptoms more than twice weekly were eligible for this study. In all, 60 patients were randomized to receive mosapride 5 mg thrice daily combined with omeprazole 10 mg once daily (GO group), or omeprazole alone (O group) for 4 weeks. The patients completed the frequency scale for the symptoms of GERD (FSSG) at the beginning and the end of the study. The primary outcome compared changes in the FSSG reflux-related symptom (RS) score between treatment groups during the study period. The FSSG RS scores significantly decreased both in the GO group and the O group, with no differences in improvement between the groups (-5.86 for the GO group vs -4.89 for the O group, P = 0.49). In non-erosive reflux disease (NERD) patients the improvement was significantly lower than that in erosive GERD patients (-4.00 vs -7.67, P = 0.02). However, the addition of mosapride was effective in subgroup analyses of specific symptoms, such as burping. Combining mosapride with PPI provided no additional amelioration of reflux symptoms compared to PPI alone. Both regimens provided less relief from reflux symptoms in NERD than in erosive GERD patients. The addition of mosapride ameliorated reflux in patients with symptoms like burping.