OBJECTIVES: Ulcerative colitis (UC) is a chronic inflammatory disease of the large intestine and rectum. Symptoms such as abdominal pain, diarrhea, and the persistent urge to defecate can impair UC patients’ physical and socio-psychological well-being. This study examined the magnitude of this impairment, and the degree to which treatment improved health-related quality of life (HRQL), of mild-to-moderate UC patients relative to a US general population sample.   METHODS: Short-Form (SF)-12v2 baseline and endpoint scores were collected from a multicenter, open-label study in which patients with active mild-to-moderate UC received multi-matrix (MMX) mesalamine 2.4–4.8g/day QD for 8 weeks. Patients were compared with a 2009 US general population sample derived from an Internet-based survey administered to a representative national sample of adults. The normative sample was matched to the age and sex of the patient sample using least squares regression. Analysis of variance models tested for significant differences between UC patients’ mean scores and normative sample’s estimated scores at each time. Group comparisons on physical and mental summary scores (PCS and MCS, respectively) relative to established minimally significant differences (MID) of 3 points identified clinically meaningful group differences.     RESULTS: Baseline SF-12v2 scores for UC patients were significantly below the matched general population on 7 of 8 subscales (all P<0.01 except for mental health, P>0.05) and on both summary measures (PCS: 45.4 vs. 50.4, P<0.001; MCS: 47.3 vs. 49.4, P<0.05). Sample differences for PCS scores but not MCS scores exceeded the established MID. At 8 weeks, SF-12v2 scores of the treated UC patients were either statistically equivalent to or exceeded norm scores. CONCLUSIONS: Active UC negatively impacted almost all dimensions of HRQL; the burden in physical health dimension was larger than the burden in mental health. Eight weeks of daily MMX mesalamine treatment improved patients to “normal” levels of functioning and well-being.