BACKGROUND & AIMS: Thiazolidinedione ligands for the gamma subtype of peroxisome proliferator-activated receptors (PPARgamma), widely used to treat type 2 diabetes mellitus, have been proposed as novel therapies for ulcerative colitis (UC). METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial compared the efficacy of rosiglitazone (Avandia; GlaxoSmithKline, Philadelphia, PA) 4 mg orally twice daily vs placebo twice daily for 12 weeks in 105 patients with mild to moderately active UC. Disease activity was measured with the Mayo score. The primary end point was clinical response (>/=2-point reduction) at week 12. Clinical remission (Mayo score and 1 patient (2%) treated with placebo (P = .01). Endoscopic remission was uncommon in either treatment arm (8% rosiglitazone vs 2% placebo; P = .34). Clinical improvement was evident as early as 4 weeks after beginning treatment (P = .049). Quality of life was improved significantly at week 8 (P = .01), but not at week 4 (P = .48) or week 12 (P = .14). Serious adverse events were rare. CONCLUSIONS: Rosiglitazone was efficacious in the treatment of mild to moderately active UC.