Background and Aims: YKP10811, a selective agonist of the serotonin 5-hydroxytryptamine-4 receptor, increases gastrointestinal (GI) motility. We investigated the safety and effects of YKP10811 on GI and colonic transit and bowel movements (BMs) in patients with functional constipation in a randomized, double-blind, placebo-controlled study. Methods: Patients with functional constipation, based on the Rome III criteria, were assigned randomly to groups given YKP10811 10 mg (n= 15), 20 mg (n= 16), 30 mg (n= 15), or placebo (n= 11) daily for 8 days. Transit of solids was measured by validated scintigraphy at baseline and on days 7 to 9. Patients kept diaries on days 1 to 9, recording time to first BM, number of BMs/day, and stool consistency (based on the Bristol Stool Form Scale). To evaluate safety, we collected data on adverse events and clinical laboratory test and electrocardiograms results. The primary efficacy end points were determined from an intent-to-treat analysis assessing colonic transit at 24 hours and the half-time (t1/2) of gastric emptying, using analysis of covariance models. Secondary efficacy end points included measures of colonic transit (geometric center at 4 and 24 hours), small-bowel transit (based on colon filling at 6 hours), t1/2 of ascending colon emptying, and bowel functions. We used the Dunnett test to compare the effects of each dose with placebo. A per-protocol analysis (PPA) assessed the t1/2 of gastric emptying and time to first BM using proportional hazards models. Results: Fifty-five participants completed the study. YKP10811 was associated with a significant acceleration in colon filling at 6 hours (P < .05), t1/2 of ascending colon emptying, and colonic transit at 24 and 48 hours, as well as increased stool consistency over 8 days (based on intent-to-treat analysis). In general, the 10-mg and 20-mg doses were the most effective in accelerating colonic transit. No serious adverse events were observed. Conclusions: YKP10811, a selective agonist of the serotonin receptor 5-hydroxytryptamine-4, accelerates GI and colonic transit and improves bowel functions in patients with functional constipation, compared with placebo. ClinicalTrial.Gov: NCT01523184.