Clinical and radiologic variables associated with perianal fistula (PAF) outcomes are poorly understood. We developed prediction models for anti-TNF treatment failure in patients with Crohn's disease related PAF.In a multicenter retrospective study between 2005 and 2022 we included biologic naïve adults (>17 years) who initiated their first anti-TNF therapy for PAF after pelvic MRI. Pre-treatment MRI studies were prospectively re-read centrally by blinded radiologists. We developed and internally validated a prediction model based on clinical and radiologic parameters to predict the likelihood of anti-TNF treatment failure, clinically, at 6 months. We compared our model and a simplified version of MRI parameters alone with existing imaging-based PAF activity indices (MAGNIFI-CD and modified Van Assche MRI scores (mVAS)) by De Long statistical test.We included 221 patients: 32±14 years, 60% males, 76% complex fistulas; 68% treated with infliximab and 32% treated with adalimumab. Treatment failure occurred in 102 (46%) patients. Our prediction model included age at PAF diagnosis, time to initiate anti-TNF treatment and smoking and 8 MRI characteristics (supra/extrasphincteric anatomy, fistula length >4.3cm, primary tracts >1, secondary tracts >1, external openings >1, tract hyperintensity on T1 weighted imaging, horseshoe anatomy, and collections >1.3 cm). Our full and simplified MRI models had fair discriminatory capacity for anti-TNF treatment failure (concordance statistic, 0.67 and 0.65 respectively) and outperformed MAGNIFI-CD (p=0.002 and <0.0005) and mVAS (p <0.0001 and <0.0001) respectively.Our risk prediction models consisting of clinical and/or radiologic variables accurately predict treatment failure in patients with PAF.