BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are complex, inflammatory bowel diseases (IBD) with debilitating complications. While severe IBD typically requires biologic agents, the optimal therapy for mild-moderate IBD is less clear. AIMS: To assess the efficacy of thiopurine monotherapy for maintenance of mild-moderate IBD and clinical variables associated with treatment outcome. METHODS: This retrospective study included adults with mild-moderate IBD who were started on thiopurines without biologic therapy. The primary outcome was therapy failure, defined by disease progression based on clinical, endoscopic, and radiologic criteria. Clinical variables were extracted at time of thiopurine initiation. Univariable and multivariable Cox proportional hazards models were used to examine the independent contribution of the clinical variables on treatment response. RESULTS: From 230 CD patients, 64 (72%) were free of treatment failure with mean follow-up of 3.3 years. In our multivariable model, thiopurine failure was associated with concomitant systemic steroid administration (aHR 2.43, p = 0.001), whereas protective factors included concomitant oral 5-aminosalicylic acid (5-ASA) therapy (aHR 0.54, p = 0.02) and non-fistulizing, non-stricturing disease (aHR 0.57, p = 0.047). From 173 UC patients, 50 (71%) were free from treatment failure with mean follow-up of 3.3 years. On multivariable analysis, concomitant oral steroids were associated with thiopurine failure (aHR 2.71, p = 0.001). Only 13 (4%) discontinued thiopurines from adverse effects. CONCLUSIONS: In mild-moderate uncomplicated IBD, thiopurine monotherapy was associated with longitudinal maintenance of remission and may represent a lower-cost, convenient, and effective alternative to biologics. Multiple clinical variables were predictive of treatment response.