Currently, a diagnostic strategy for selecting appropriate patients for termination of proton pump inhibitor (PPI) therapy is not available. To determine the clinical utility of prolonged wireless reflux monitoring in predicting which patients can stop PPI therapy, researchers conducted a double-blinded clinical trial for 3 years at two centers. The study team enrolled adults with esophageal symptoms of heartburn, regurgitation, and/or chest pain, as well as an insufficient response to PPI therapy. Participants underwent sustained wireless reflux monitoring—staying off PPIs for 7 or more days—and a 3-week PPI cessation intervention. The primary outcome was tolerance of PPI cessation, determined by discontinuation or reuptake of PPIs, and symptom burden was measured with the Reflux Symptom Questionnaire Electronic Diary (RESQ-eD). Among 100 participants who met the inclusion criteria, 34% discontinued PPIs. The greatest indicator of PPI discontinuation was the number of days with an acid exposure time (AET) greater than 4.0% (OR, 1.82; P<.001). Participants with 0 days of AET greater than 4.0% had 10-fold greater odds of stopping PPI therapy than participants with 4 days of AET greater than 4.0%. Decline in symptom burden was higher in the discontinued PPI group compared with the resumed PPI group (RESQ-eD, -43.7% vs -5.3%; P=.04).