Objective: Patients in most trials of pharmacotherapy for nonorganic dyspepsia have been groups referred selectively for endoscopy, which could have led to a selection bias of nonresponders, explaining the negative outcome of most controlled treatment trials in nonorganic dyspepsia. The aim of this study was to evaluate the effects of cisapride and nizatidine in patients with nonorganic dyspepsia who were recruited directly from primary care settings, and to evaluate the therapeutic implications of dyspepsia subgrouping. Methods: A consecutive series of patients who consulted their general practitioner with dyspepsia were invited to an interview and endoscopy. Before endoscopy, symptoms were classified as reflux-like, dysmotility-like, ulcer-like, or unclassifiable. A total of 330 patients with either minor or no abnormalities at endoscopy were randomized to double blind treatment with cisapride 10 mg t.i.d., nizatidine 300 mg at night, or placebo for 2 wk. Results: A symptomatic response was found in 62% of patients on cisapride (therapeutic gain cisapride vs placebo: 0.1% [95% confidence interval -14% to 14%]) and in 54% of patients on nizatidine (therapeutic gain nizatidine vs placebo: -8% [95% confidence interval -22% to 7%]). Response to treatment was independent of symptom classification. Conclusions: The effects of a 2-wk course of cisapride or nizatidine in unselected patients with dyspepsia recruited from primary care were not superior to those of placebo. Symptom subgrouping was not predictive of response to therapy.