OBJECTIVE: H 2 receptor antagonist therapy has been shown to produce rebound acid hypersecretion. The clinical significance of this phenomenon is not known. We performed this study to determine whether withdrawal of H 2 receptor antagonist therapy results in dyspepsia in previously asymptomatic volunteers. METHODS: Thirty-five Helicobacter pylori-positive asymptomatic volunteers were randomized in double-blind fashion to receive 2 months’ treatment with either ranitidine 300 mg nocte or placebo. Dyspeptic symptoms were measured before starting treatment and over the course of 10 days after stopping treatment by means of a validated questionnaire. RESULTS: Thirty-one subjects completed the study; 17 were randomized to ranitidine. The pretreatment median aggregate dyspepsia score of the placebo group was 0 (0–4), as was that of the ranitidine group (0–8) (N.S.). During the 10 days after completion of ranitidine, the median aggregate dyspepsia score was 1.4 (0–30), compared with 0 (0–6.3) after placebo ( p < 0.01). Of those given ranitidine, 59% experienced dyspepsia after treatment, compared with only 14% who took placebo. In the subgroup that developed dyspepsia after active therapy, the median duration of symptoms was 2 days, symptom severity being maximal on the second day after completion of the tablets. On the days when dyspepsia was experienced, the median daily dyspepsia score was 5 (range, 2–10), which was similar to that of a control group with active duodenal ulcer disease (5; range, 0–11). CONCLUSIONS: Withdrawal of a 2-month course of ranitidine 300 mg nocte results in the development of dyspeptic symptoms in a proportion of previously asymptomatic subjects. Patients receiving ranitidine should be warned about this rebound dyspepsia and advised not to immediately resume treatment, as rebound symptoms are likely to improve within a few days.