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The aim of the study was to investigate whether hydrotalcite was comparable to esomeprazole, a proton pump inhibitor, in on-demand therapy for non-erosive reflux disease (NERD).This was a multicenter, randomized, open-label clinical trial with initial and on-demand therapy. Patients who had complete symptom relief in the initial therapy were randomized to either hydrotalcite or esomeprazole in the on-demand therapy. The percentage of patients who quit on-demand therapy in the two groups and the cost-effectiveness of the treatment were evaluated as primary end points. The rate of symptom relief and the improvement of symptom score for initial therapy and the weekly average symptom score and weekly average number of days on treatment for on-demand therapy were evaluated as secondary end points.In total, 398 patients were recruited in the initial therapy group, among whom 253 were included in on-demand therapy, with 127 patients in the hydrotalcite group and the remaining 126 in the esomeprazole group. 14 (11.0%) patients in the hydrotalcite group and six (4.8%) in the esomeprazole group quit the on-demand therapy due to unsatisfactory symptom control (P = 0.065). Cost-effectiveness calculated as the ratio of the cost of hydrotalcite to that of esomeprazole (per person/day) was 35.3% in the on-demand therapy. Similar number of patients achieved symptom relief in both groups.Hydrotalcite is a good option of on-demand therapy for NERD patients due to its cost-effectiveness and speed of action.