Nonresponse to proton pump inhibitors (PPI) concerns up to 40% of patients treated for gastroesophageal reflux disease (GERD). Identifying predictive factors of nonresponse might help to optimize patients' treatment. The aim of this study was to determine clinical factors associated with nonresponse to PPI therapy in patients referred for pH-impedance monitoring. One hundred and sixty-eight consecutive patients (105 females, mean age 52 years, range 17-83) were included between October 2011 and May 2013. Before the realization of high-resolution manometry and 24-hour pH-impedance monitoring they completed a questionnaire including Rome III criteria for functional dyspepsia and irritable bowel syndrome (IBS). Comparisons between patients with and without PPI response were performed using chi-square or analysis of variance tests. One hundred and twenty-six patients (83%) were considered as PPI nonresponders and 26 (17%) as responders. No significant difference was observed for age and body mass index. No manometric and pH-impedance profiles were identified as associated with PPI response. The percentage of patients with functional dyspepsia and IBS was higher in PPI nonresponders patients than in responders (65.6% and 27.2%, respectively, vs. 38.5% and 7.7%, P = 0.01 and P = 0.03). This study confirms that functional digestive disorders are more frequent in patients with persistent GERD symptoms on PPI and they might be indicative of nonresponse to PPI therapy.