Abstract Impaired gastric accommodation, hypersensitivity to distension and delayed gastric emptying are major pathophysiological mechanisms in functional dyspepsia (FD). Acotiamide (Z‐338) was well‐tolerated in healthy volunteers. To determine the effect of three doses of Acotiamide on major pathophysiological mechanisms, symptoms, quality of life (QOL) and safety in functional dyspeptics. A phase IIa, randomized, double‐blind, placebo‐controlled study (14, 21 and 28 days, respectively, for run‐in, study drug administration and follow‐up). Gastric accommodation, sensitivity to distension and gastric emptying were assessed by barostat and13C breath test, symptoms by daily diary cards and QOL by SF‐36. A total of 71 patients were enrolled (62 evaluable). There was no effect on gastric emptying and sensitivity to distension. 300 mg was better than placebo for meal accommodation (P = 0.024). 100 mg was better than placebo at week 2 for upper abdominal bloating (P = 0.001) and overall symptom score (P = 0.022), and at week 3 for bloating (P = 0.008) and heartburn (P = 0.041). 100 mg was also better than placebo for QOL (physical function) (P = 0.003). Acotiamide was safe and well‐tolerated in patients with FD. The involved mechanism could at least in part depend on an effect on meal‐induced accommodation. 100 mg Acotiamide exhibited the potential to improve FD symptoms and QOL. Further studies are indicated.