Background/Aim: To investigate patient-reported health-related quality of life (HRQoL) in data collected from a multinational randomized double-blind controlled trial comparing oral mesalazine (4 g) + topical mesalazine enema (1 g) to oral mesalazine alone (4 g). Methods: HRQoL was collected using the EQ-5D at baseline and weeks 2, 4 and 8. The EQ-5D assesses mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Scores from each dimension were reported individually, and converted into a weighted health state which reflects an individual’s perception of their health condition. Results: At week 4, a significant HRQoL improvement was observed for patients on mesalazine enemas compared to placebo enemas, with EQ-5D scores of 0.906 and 0.838, respectively (p < 0.05). Mesalazine enema was found to reduce the probability of impairment at week 4 for mobility (p = 0.049) and anxiety/depression (p = 0.048), and was of borderline significance for pain/discomfort (p = 0.053); there was also an increased probability of influencing HRQoL changes for mobility (p < 0.005), usual activities (p < 0.005), pain/discomfort (p < 0.005) and anxiety/depression (p < 0.005), based on reported HRQoL problems at baseline. Conclusions: Including 1 g mesalazine enemas with 4 g oral mesalazine significantly improved HRQoL in patients with active ulcerative colitis. The improvement in QoL of patients with UC preceded clinical remission, and this underlines the importance of including QoL instruments in clinical studies.