BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Corticosteroids and 5-aminosalicylates are the most commonly used therapies. However, many patients require immunosuppressive therapy for steroid-refractory and steroid-dependent disease. Methotrexate is a medication that is effective for treating a variety of inflammatory diseases, including Crohn's disease. This review was performed to determine the effectiveness of methotrexate treatment in UC patients. This review is an update of a previously published Cochrane review. OBJECTIVES: To assess the efficacy and safety of methotrexate for induction of remission in patients with UC. SEARCH METHODS: MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized trials register were searched from from inception to June 26, 2014. Study references and review papers were also searched for additional trials. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only. SELECTION CRITERIA: Randomized controlled trials comparing methotrexate with placebo or an active comparator in patients with active ulcerative colitis were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed studies for eligibility, extracted data and assessed study quality using the Cochrane risk of bias tool. The primary outcome measure was the proportion of patients who achieved clinical remission and withdrawal from steroids as defined by the studies and expressed as a percentage of the total number of patients randomized (intention-to-treat analysis). We calculated the risk ratio (RR) and corresponding 95% confidence intervals (95% CI) for dichotomous outcomes. The overall quality of the evidence supporting the primary outcome was assessed using the GRADE criteria. MAIN RESULTS: Two studies (n = 101 patients) were included in the review. One study (n = 67) compared oral methotrexate 12.5 mg/week) to placebo. The other study (n = 34) compared oral methotrexate (15 mg/week) to 6-mercaptopurine (1.5 mg/kg/day) and 5-aminosalicylic acid (3 g/day). The placebo-controlled study was judged to be at low risk of bias. The other study was judged to be at high risk of bias due to an open-label design. There was no statistically significant difference in clinical remission rates between methotrexate and placebo patients. Forty-seven per cent (14/30) of methotrexate patients achieved clinical remission and complete withdrawal from steroids during the study period compared to 49% (18/37) of placebo patients (RR 0.96, 95% CI 0.58 to 1.59. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (32 events). There were no statistically significant differences in the proportion of patients who achieved clinical remission and withdrawal from steroids in the study comparing oral methotrexate to 6-mercaptopurine and 5-aminosalicylic acid. At 30 weeks, 58% (7/12) of methotrexate patients achieved clinical remission and withdrawal from steroids compared to 79% (11/14) of 6-mercaptopurine patients (RR 0.74, 95% CI 0.43 to 1.29) and 25% of 5-aminosalicylic acid patients (RR 2.33, 95% CI 0.64 to 8.49). GRADE analyses indicated that the overall quality of the evidence was very low due to very sparse data (18 and 9 events respectively) and and high risk of bias. In the placebo-controlled trial two patients (7%) were withdrawn from the methotrexate group due to adverse events (leucopenia, migraine) compared to one patient (3%) who had a rash in the placebo group (RR 2.47, 95% CI 0.23 to 25.91). Adverse events experienced by methotrexate patients in the active comparator study included nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia. AUTHORS' CONCLUSIONS: Although methotrexate was well-tolerated, the studies showed no benefit for methotrexate over placebo or active comparators. The results for efficacy outcomes between methotrexate and placebo, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration would be effective for induction therapy is unknown. At present there is no evidence supporting the use of methotrexate for induction of remission in active ulcerative colitis. A trial in which larger numbers of patients receive a higher dose of oral methotrexate should be considered. Currently there are two large ongoing placebo-controlled trials (METEOR and MERIT-UC) assessing the efficacy and safety of intramuscular or subcutaneous methotrexate in patients with active UC which may help resolve the evidence supporting the use of methotrexate as therapy for active of ulcerative colitis.