Levosulpiride is a benzamide derivate D(2) dopamine antagonist with prokinetic activity that can accelerate gastric emptying and reduce discomfort in response to gastric distention. The aim of the study is to compare the clinical efficacy of levosulpiride and cisapride in patients with dysmotility-like functional dyspepsia. In a exploratory pilot study performed as a multicenter, randomized, double-masked trial, the effects of 8 weeks of treatment with either levosulpiride, 25 mg, 3 times daily (n = 69) or cisapride, 10 mg, 3 times daily (n = 71) were compared. Individual symptoms (pain/discomfort, fullness, bloating, early satiety, and nausea/vomiting), global symptom score, effect on health-related quality of life (HRQoL), and anxiety-state and anxiety-trait were evaluated. Adverse events also were recorded. Both levosulpiride and cisapride improved dyspeptic symptoms and decreased total symptom score (79.9% and 71.3%, respectively); no significant statistical difference between treatments was found (P = 0.07 for total symptom score). HRQoL improved similarly after both treatments, whereas no change was observed in anxiety. Medication-related adverse effects were present in 13 of 69 patients (18.8%) in the levosulpiride group and 8 of 71 patients (11.3%) in the cisapride group. Significantly more (P = 0.03) patients treated with cisapride had to abandon the trial because of side effects. Levosulpiride is at least as effective as cisapride in the treatment of dysmotility-like functional dyspepsia.