Introduction Different phenotypes of GERD-suspected patients who do not respond to proton pump inhibitor (PPI) therapy might be identified using pH-impedance monitoring. Our aim was to describe demographic, manometric and impedance patterns associated with phenotypes of PPI non-responders. Patients and methods PPI non-responders (without previous foregut surgery, scleroderma or achalasia) referred for 24-h esophageal pH-impedance monitoring on PPI were recruited. Demographic data, results of upper GI endoscopy and high resolution manometry were collected. Two investigators reviewed pH-impedance studies; a 3rd one arbitrated disagreements. Based on impedance pattern, reflux events were characterized as belch, supragastric belch, reflux starting with belch, reflux induced by supragastric belch, reflux associated with belch, reflux associated with supragastric belch, proximal liquid reflux, swallow-induced reflux, distal liquid reflux. Patients were classified into 3 groups: persistent acid reflux (acid esophageal exposure time (AET; esophageal pH 5% of total time), reflux sensitive esophagus (AET<5%, symptom index (SI)≥50%), and functional heartburn (AET<5%, SI<50%, absence of Barrett's esophagus). Data are presented as percentage or median (range) and compared using Chi2 or Mann Whitney test. Results Eighty PPI non-responders (30 males, mean age 51 years (range 19-76), mean body mass index (BMI) 29.5 kg/m2 (range 18.6-44.1)) were included. AET was 0.5% (0.0-35.5) of total time and median number of reflux events (liquid, gas or mixed) was 45 (4-221). Eight patients (10%) had persistent acid reflux, 29 (36.2%) reflux sensitive esophagus and 43 (53.8%) functional heartburn. Characteristics of these groups are described in Table 1. Patients with persistent acid reflux had less frequently normal esophageal motility than the other patients groups (29% vs 46%, p<0.01). Patients with reflux sensitive esophagus or functional heartburn tended to present more frequently supra-gastric belch than patients with persistent acid reflux (60% vs 25, p=0.067). Distribution of dominant impedance patterns is presented in the Table 2. Conclusions The mechanistic reflux profile in PPI non-responders is heterogeneous. Although liquid reflux events were the most common mechanism of reflux in all three PPI non-responder subtypes, patients with reflux sensitivity and functional heartburn had much more variability in their mechanistic profile with a large proportion being associated with both suband supra-gastric belching. These different mechanistic profiles may have clinical implications as therapy targeting the dominant mechanism in each patient may be more effective. Table 1