Patients who are unresponsive to 4-8 weeks' treatment with PPIs twice daily might have so-called refractory GERD. The first investigation these patients should undergo is upper endoscopy to exclude a diagnosis of peptic ulcer disease or cancer and identify the presence of esophagitis. The presence of esophagitis in these patients is suggestive of a pill-induced injury, an autoimmune skin disease involving the esophagus, eosinophilic esophagitis or, less likely, a hypersecretory syndrome or a genotype that confers altered metabolism of PPIs. Refractory reflux syndromes associated with normal endoscopy findings are more problematic to diagnose and further testing may be required, including prolonged 48 h pH testing, impedance measurements (for nonacid reflux), esophageal manometry and gastric function tests. For patients with refractory GERD who do not have esophagitis, possible etiologies include nocturnal gastric acid breakthrough, nonacid GER, missed GER or other diseases such as achalasia, gastroparesis or functional heartburn.