OBJECTIVES:  To investigate whether plecanatide, a uroguanylin analog, improved health-related quality of life (HRQoL) in 2 clinical trials of patients with chronic idiopathic constipation (CIC). METHODS:  : Patients meeting modified Rome III CIC criteria were randomized to placebo, plecanatide 3mg or 6mg daily for 12 weeks. The primary endpoint was the proportion of durable overall CSBM responders (≥3 CSBMs plus increase of ≥1 CSBM over baseline in the same week) for ≥9 of 12 treatment weeks, including ≥3 of the last 4 weeks. HRQoL assessments included: Patient Assessment of Constipation-Symptoms (PAC-SYM), PAC-Quality of Life (PAC-QOL), and Treatment Satisfaction. Results are versus placebo. RESULTS:  Patients (N=2683) had similar baseline characteristics. Pooled efficacy showed significantly greater overall durable CSBM responders with plecanatide 3mg (n=184, 20.5%) and 6mg (n=176, 19.8%) vs placebo (n=103, 11.5%; P<.001 both doses). Significant increases in CSBMs were seen during Week 1 and were maintained through Week 12. Plecanatide 3mg and 6mg significantly improved PAC-SYM at Weeks 4, 8 and 12 in both studies, with a mean change differences at Week 12 of –0.22 (P<.001) and –0.23 (P<.001) [Study 1] and –0.18 (P=.002) and –0.15 (P=.009) [Study 2]. A similar improvement in PAC-QOL was noted for both doses at Weeks 4, 8 and 12 in both studies; the mean change differences at Week 12 for plecanatide 3mg and 6mg were –0.25 (P<.001) and –0.28 (P<.001) [Study 1] and –0.20 (P<.001) and –0.19 (P=.001) [Study 2]. Plecanatide yielded significantly (P≤.001) higher mean treatment satisfaction scores at each assessment point and increased over time. CONCLUSIONS:  Plecanatide 3mg and 6mg significantly improved bowel symptoms and HRQoL at all time points and increased the proportion of durable overall CSBM responders. These data suggest plecanatide improves constipation and HRQoL, and therefore may offer a promising new treatment option for CIC patients.