Prucalopride, a first-in-class dihydrobenzofuran-carboxamide derivative, is a potent, selective and specific serotonin 5-HT(4) receptor agonist with enterokinetic properties. Over a 12-week treatment period, prucalopride 2 and 4 mg once daily significantly improved bowel habit assessments (based on patient diary data) relative to placebo in three large, randomized, double-blind, multicentre trials in patients (aged 17-95 years) with severe chronic constipation, the majority of whom were women who experienced inadequate relief with previous therapies. There was no additional benefit with the 4 mg/day over the 2 mg/day dosage of prucalopride. Patient assessments of constipation symptoms and severity, treatment efficacy, satisfaction with bowel habit and treatment, and health-related quality of life were also significantly improved with prucalopride compared with placebo. The improvement in patient satisfaction with bowel habit and treatment was maintained for up to 24 months in open-label, multicentre, long-term follow-up studies. Prucalopride therapy was generally well tolerated; most adverse events in the 12-week studies were transient and of mild to moderate severity. In terms of cardiovascular tolerability, the incidence of QT interval prolongation with prucalopride at dosages of 2 and 4 mg/day was low and similar to that with placebo. Moreover, prucalopride at dosages up to 20 mg/day (10-fold higher than the recommended therapeutic dosage) had no clinically relevant effects on cardiovascular parameters in healthy volunteers.