OBJECTIVES: Chronic constipation (CC), a common functional gastrointestinal disorder, has laxatives as its mainstay of treatment. Refractoriness to laxatives calls for better treatment options. Prucalopride is a novel, well-tolerated enterokinetic with high 5-hydroxytryptamine 4 receptor selectivity. This study was undertaken with the intention to establish the efficacy and safety of prucalopride with placebo in adults with refractory CC. MATERIALS AND METHODS: Patients were screened and 180 patients fulfilling the inclusion criteria were simply randomized into 2 groups either to receive prucalopride 2 mg (n = 90) or placebo (n = 90) once daily for a duration of 12 weeks. The efficacy endpoints (primary) were intended to measure the proportion of patients with three or more spontaneous complete bowel movements (SCBMs) per week over 12 weeks. Secondary endpoints were assessed via the validated questionnaires. Adverse events, electrocardiogram, and other laboratory parameters were monitored at different time intervals. RESULTS: Efficacy and safety were analyzed in 180 patients simply randomized (1:1) into group A (prucalopride arm, n = 90) and group B (placebo arm, n = 90). Patients having three or more SCBMs per week in the prucalopride arm (2 mg) were 41% as against to 12% in the placebo arm (P < 0.001). A significant increase (P < 0.001) in the number of spontaneous bowel movements per week plus an increase of average bowel movement by 1 point per week was seen in the prucalopride arm. Secondary efficacy endpoints which included patients' treatment satisfaction, improvement in the perception of constipation symptoms using the patient assessment of constipation -symptoms and stool consistency score changes were more pronounced in the prucalopride arm than the placebo. The most common adverse events reported from both the groups were headache, nausea, bloating, and diarrhea. No significant cardiovascular changes or laboratory abnormality was detected throughout the study period. CONCLUSION: Prucalopride is effective in laxative refractory CC cases with a good safety profile.