BACKGROUND: Positive symptom association probability (SAP) with physiologic esophageal acid exposure time (AET) on pH-impedance monitoring defines reflux hypersensitivity (RH), a correlate of acid sensitivity on pH monitoring. We evaluated prevalence, clinical characteristics, and symptomatic outcomes of RH in a prospective observational cohort with reflux symptoms undergoing pH-impedance monitoring. METHODS: Reflux hypersensitivity was diagnosed when SAP was positive with pH- and/or impedance-detected reflux events with physiologic AET. Symptom burden was assessed using dominant symptom intensity (DSI, product of symptom severity and frequency on 5-point Likert scales) and global symptom severity (GSS, global esophageal symptoms on 100-mm visual analog scales) by questionnaire, both at baseline and on prospective follow-up. Clinical characteristics and predictors of symptomatic improvement were assessed with univariate and multivariate analyses. KEY RESULTS: Seventy-seven patients (29%) met criteria for RH, of which 53 patients (53.7 ± 1.8 years, 66% F) were contacted after 3.3 ± 0.2 years for follow-up. Reflux hypersensitivity was detected on pH-impedance testing both on and off antisecretory therapy; pH alone missed 51% of RH. About 57% reported ≥50% GSS improvement. Sixteen patients undergoing antireflux surgery (ARS) reported better symptom improvement compared to 37 patients treated medically (GSS change: p = 0.005; DSI change: p = 0.04). Hiatus hernia (p = 0.03) and surgical management (p ≤ 0.04) predicted symptom improvement on univariate analysis, while acid sensitivity was a negative predictor for outcome on both univariate (p = 0.02) and multivariate analyses (p ≤ 0.04). CONCLUSIONS & INFERENCES: Reflux hypersensitivity is a mechanism for persistent reflux symptoms in almost one-third of patients undergoing pH-impedance testing. While acid sensitivity predicts suboptimal symptom improvement, antireflux therapy may improve RH in select settings.