<i>Background:</i> A definitive treatment for functional dyspepsia (FD), and the role of <i>Helicobacter pylori</i> eradication on the course of this disease are controversial. <i>Aim:</i> To investigate the effect of a combination of acid-suppressing and prokinetic drugs or eradication therapy on the course of <i>H. pylori</i>-positive FD. <i>Method:</i> A total of 157 patients with endoscopically-proven <i>H. pylori</i>-positive FD and no response to 4 weeks of antacid therapy were randomly divided into 2 groups. 84 were placed on bismuth subnitrate plus metronidazole and amoxicillin (group A) and 73 received ranitidine and metoclopramide for 4 weeks (group B). The severity of symptoms (7 items) were assessed on a 6-point categorical scale. Group B patients who failed to respond to their medication underwent eradication therapy after 3 months. All patients were followed and assessed for 9 months after the end of therapy by the same clinicians who initiated the therapy. <i>Results:</i> At the end of the medication period, symptom’s score decreased significantly, and to the same extent. At 3-month follow-up moderate or complete response was achieved in 27.4% (group A) and 19.2% (group B) by intention-to-treat analysis. 34 patients of group B, not responding to treatment, underwent eradication therapy and followed as group A. Eradication of <i>H. pylori</i> was successful in 60 of 110 controlled patients (54%). After 9-month follow-up, complete or moderate response was observed in only 30% of 60 patients in whom <i>H. pylori</i> had been eradicated (intention-to-treat analysis), compared to 38% in 50 noneradicated cases (p > 0.05, 95% CI: 19–43 vs. 24–52). <i>Conclusion:</i> Eradication therapy with bismuth compound is effective as ranitidine plus metoclopramide in a subgroup of patients with FD not responding to antacid therapy. There is no difference in improvement between patients cured or not cured from <i>H. pylori</i> infection. This suggests that bismuth compounds were effective in FD when used in the eradication regimen. Combination therapy with acid-suppressing drugs plus prokinetic and bismuth seems to hold promise for FD.