BACKGROUND: Patients with proton pump inhibitor (PPI)-resistant nonerosive reflux disease (NERD) include subgroups that have markedly different pathophysiology. This study aimed to clarify the pathophysiology of NERD by esophageal manometry with 24-hour esophageal impedance and pH monitoring. METHODS: Eighteen consecutive outpatients referred to our expert center for functional gastrointestinal motility with suspected PPI-resistant NERD were enrolled. Manometry was performed to detect esophageal motility disorders. Subsequently, 24-hour esophageal impedance and pH monitoring was done while patients were on PPI therapy. RESULTS: Manometry revealed 1 case of achalasia, 1 case of nutcracker esophagus and 3 cases of diffuse esophageal spasm. Three patients had ineffective esophageal motility, with impedance and pH monitoring being performed in 2 of them. Esophageal acid exposure (%time pH <4) was normal in both, but the symptom index (SI) was positive for nonacidic reflux in 1 patient. One of the 10 patients with normal esophageal motility had abnormal esophageal acid exposure. The SI was positive for weakly acidic and nonacidic reflux in 3 of the remaining 9 patients with normal esophageal acid exposure. Five of the other 6 patients seemed to have functional heartburn. CONCLUSION: A substantial percentage (28%) of patients with suspected PPI-resistant NERD had primary esophageal motility disorders. Both nonacidic reflux and weakly acidic reflux are important contributors to the symptoms of patients with PPI-resistant NERD. Esophageal manometry is required to exclude motility disorders, while 24-hour esophageal impedance and pH monitoring is invaluable for assessing symptom-reflux associations and the indications for fundoplication in patients with suspected PPI-resistant NERD.