OBJECTIVES:  Studies of patients with ulcerative colitis (UC) have established that reduction in clinical symptoms and endoscopic activity each independently predict improved health-related quality of life (HRQL). However, the combined impact of these factors on HRQL has not been examined, nor whether histologic activity predicts HRQL. The current analysis examines individual and combined associations of these 3 types of disease activity with HRQL. METHODS:  Post hoc, exploratory analyses were conducted on data from patients with active mild-to-moderate UC in an open-label trial who received 8 weeks of treatment with 4.8 g/day of multimatrix mesalamine once daily. Outcomes assessed at baseline and final visits included clinical and endoscopic activity (UC Disease Activity Index [UC-DAI]); histologic activity index (modified Geboes’ scoring); disease-specific HRQL (Short Inflammatory Bowel Disease Questionnaire [SIBDQ]); and generic HRQL (SF-12v2^® Health Survey [SF-12v2]). The individual impact of each type of disease activity on HRQL was examined by comparing changes in SIBDQ and SF-12v2 scores between subgroups classified by disease activity status (eg, achieving clinical remission), while their combined impact was tested using multivariable regression. Hochberg adjusted P values controlled for Type I error.  RESULTS:  Improvements in SIBDQ and SF-12v2 domains were significantly larger for patients with clinically meaningful improvements in clinical and endoscopic activity (all P<0.001), patients with lower histologic activity index scores (all P<0.05), and patients in clinical and endoscopic remission compared to endoscopic remission only (all P<0.05). Findings from regression models indicated that decreased clinical and endoscopic activity, though not histologic activity, uniquely predicted improvement in SIBDQ and SF-12v2 domains. CONCLUSIONS:  Clinical, endoscopic, and histologic activity have separable, and in some cases additive impacts on UC patients’ HRQL. Treatments impacting multiple types of disease activity should result in greater improvements in patients’ functioning and well-being than treatments that target clinical, endoscopic, or histologic activity alone.