Background: Due to toxicity problems and controversial evidence, thiopurine use in ulcerative colitis (UC) has faced a lot of criticism. We present a critical review of the literature on efficacy of thiopurines in UC. Methods: Studies evaluating therapeutic efficacy of thiopurine remission induction and/or maintenance treatment in UC were identified using the Cochrane Library, MEDLINE, and EMBASE. Results: Out of 5 randomized trials on thiopurine induction treatment, 3 demonstrated a significant effect of thiopurine treatment vs mesalamine or placebo in steroid-dependent UC patients: (1) lower endoscopic activity scores, (2) higher clinical remission rates, and (3) more patients who discontinued steroids. Two found no significant difference in clinical and endoscopic remission of azathioprine compared with sulfasalazine or placebo in patients with active UC. Out of 7 randomized trials on thiopurine maintenance treatment, 4 demonstrated significant higher clinical and endoscopic remission rates in thiopurine-treated patients compared with placebo or mesalamine. Three found no significant difference in clinical and endoscopic remission of thiopurine maintenance treatment compared with sulfasalazine or placebo. Conclusions: All studies that investigated thiopurine treatment in UC had shortcomings, such as lack of sufficient power, no use of blinding, allowed concomitant treatment with steroids, and no endoscopy to confirm active disease at study entry or to evaluate therapeutic efficacy. Hence, current clinical practice of thiopurine treatment in UC is based on minimal and controversial evidence. This underscores the need for clinical studies with sufficient power and objective end points in order to determine efficacy of thiopurines in UC.