OBJECTIVES: To identify symptoms significantly impacting health-related quality of life (HRQOL) and how changes in symptoms explain variability in HRQOL among adult patients with irritable bowel syndrome with constipation (IBS-C).  METHODS: IBS-C symptom and HRQOL data were pooled from two Phase 3 trials (n=1602) assessing efficacy and safety of linaclotide, a guanylate cyclase-C agonist approved for adult treatment of IBS-C in the US and moderate to severe IBS-C in Europe. IBS-C symptoms measured included abdominal (bloating, cramping, discomfort, fullness, pain) and bowel (spontaneous bowel movement [SBM] and complete SBM [CSBM] frequency, stool consistency, and straining) symptoms. HRQOL measures included: a disease-specific Irritable Bowel Syndrome-Quality of Life questionnaire (IBS-QOL), and generic HRQOL measures, the EuroQol-5D (EQ-5D) and Short Form-12 (SF-12). Analysis of variance evaluated relationships between Week 12 change from baseline in IBS-C symptoms and HRQOL, controlling for demographics and baseline HRQOL.  RESULTS: Changes in IBS-QOL overall score were most significantly impacted by changes in abdominal fullness, cramping, and straining (beta coefficients: -1.1, -1.3, -1.7, respectively). The full model explained nearly half of the changes in IBS-QOL (R-Square: 0.42). Changes in EQ-5D were primarily driven by changes in abdominal bloating, cramping, and straining (beta coefficients: -0.009, -0.009, -0.011, respectively, R-Square: 0.49). Changes in SF-12 physical and mental component summaries (PCS and MCS) were best explained by changes in bloating, cramping, and straining (beta coefficients: -0.41, -0.34, -0.53, respectively; R-square: 0.42), and abdominal fullness and CSBM frequency (beta coefficients: -0.59 and 0.26, respectively; R-square: 0.35), respectively. CONCLUSIONS: Improvements in abdominal cramping and straining at Week 12 compared to baseline were associated with improvements in HRQOL as measured by the IBS-QOL, EQ-5D and SF-12 PCS. Improvements in abdominal bloating and fullness, and increases in CSBMs were also associated with HRQOL improvements. Targeting improvement in specific IBS-C symptoms may result in increased patient HRQOL.