OBJECTIVES: The purpose of this study was to evaluate the impact of mesalazine on patient reported QoL when administered either orally or in combination with topical treatment in patients with acute, mild-to-moderate ulcerative colitis (UC). METHODS: Data was from a randomised controlled trial where patients received daily treatment of either 4g oral mesalazine plus 1g enema mesalazine (MES+), or 4g oral mesalazine plus a placebo enema (MES-). Oral treatment was given for 8 weeks (the trial period) and enema treatment for the initial 4 weeks only. QoL was measured using the EQ-5D and administered at baseline, 2, 4, and 8 weeks. The Mann-Whitney test was used to compare means. RESULTS: 127 subjects were randomised: 60% male, mean age 43.5 years and mean EQ-5D index value 0.765 (SD 0.16). The baseline EQ-5D was 0.780 (SD 0.20) in the MES+ arm and 0.745 (SD 0.16) in the MES- arm (p=0.27). Rapid improvement in QoL was evident in both treatment arms at 2 weeks with change from baseline Db=0.079 (p<0.001) in the MES+ arm and Db=0.097 (p=0.03) in the MES- arm. However, a near normal QoL was achieved more quickly in the MES+ arm, whereby the mean QoL at 4 weeks was 0.921 (SD 0.14), versus 0.859 (SD 0.17) in the MES- arm (p=0.034). At 8 weeks, substantial improvement in QoL was evident in both treatment arms with almost normal QoL compared to the UK standard population (MES+: mean=0.922, Db= 0.15 [p<0.001] and MES-: mean=0.920, Db =0.16 [p<0.001]). CONCLUSION: Treatment with mesalazine resulted in improved QoL as measured using the EQ-5D. Near normal QoL was achieved by 8 weeks in the two treatment arms but it was achieved much faster with combination treatment of oral and enema mesalazine. Consequently combination oral and enema therapy should be offered as first line therapy for patients with mild-to-moderate UC.