There continues to be significant controversy related to diagnostic testing for gastroesophageal reflux disease (GERD). Symptoms of GERD may be associated with physiologic esophageal acid exposure measured by intraesophageal pH monitoring or pH-impedance monitoring, and a significant percentage of patients with abnormal esophageal acid (or weak acid) exposure have no or minimal clinical symptoms of reflux. On the other hand, endoscopic lesions are only present in a minority of GERD patients. In clinical practice, presumptive diagnosis of GERD is reasonably assumed by the substantial reduction or elimination of suspected reflux symptoms during the therapeutic trial of acid reduction therapy, the so-called proton pump inhibitor (PPI) test. We aimed to assess the optimal cutoff value and duration of this test in GERD patients with and without esophagitis. We conducted a prospective study of 544 patients, endoscopically investigated and treated for 2 weeks with PPIs at double dose, and for an additional 3 months at standard dose. The status of the patient at the end of the study was used as an independent diagnostic standard. We found esophagitis present in 55.8% and absent in 44.2% of patients (corresponding to a diagnosis of nonerosive reflux disease [NERD]). The test was positive in 89.7-97.8% of the patients according to the cutoff or duration of the test used. The sensitivity of the PPI test was excellent, ranging from 95.5 to 98.8%, whereas the specificity was poor, not exceeding 36.3%. Erosive esophagitis patients responded more favorably to the PPI test and subsequent PPI therapy compared with NERD patients. In conclusion, the PPI test is a sensitive but less specific test. Its optimal duration is 1 week, and the optimal cutoff value is a decrease of heartburn score of more than 75%. NERD patients respond less satisfactorily to PPIs, even when functional heartburn patients are excluded and only 'true' NERD patients are considered.