INTRODUCTION: There are spare data on comparative medication efficacy in fistulizing Crohn's disease (FCD), particularly with immunomodulator cotherapy. Persistence is a unique way to assess real-world outcomes. METHODS: The persistence of all dispensed biological agents was analyzed from the Australian Pharmaceutical Benefits Scheme registry data 2005-2021 for FCD. Propensity score matching was performed to account for baseline cohort imbalance. RESULTS: There were 5,739 lines of therapy in 4,466 patients over the 16-year period with 17,144 patient-years of follow-up; through therapy, 2,605 of 5,739 (45.4%) used adalimumab, and 3,134 of 5,739 (54.6%) used infliximab; 1,697 of 5,739 (29.6%) used thiopurine cotherapy at induction, while 242 of 5,739 (4.2%) used methotrexate. As a first-line biologic (biologic-naive), infliximab showed superior overall and corticosteroid-free persistence to adalimumab ( P = 0.0002 and P = 0.0021, respectively). Used after first-line (biologic-exposed), there was no difference between agents for overall persistence ( P = 0.064), although infliximab showed greater corticosteroid-free persistence ( P = 0.030). Coinduction with thiopurine was associated with improved overall and corticosteroid-free persistence ( P = 0.0002 and P = 0.045, respectively). After propensity score matching, infliximab showed superior overall and corticosteroid-free persistence compared with adalimumab in bio-naive ( P < 0.0001 and P = 0.0016, respectively), not in bio-exposed patients ( P = 0.12 and P = 0.074, respectively). Thiopurine was associated with superior overall and corticosteroid-free persistence use, although no difference was seen with methotrexate. DISCUSSION: The Persistence Australia National IBD Cohort with real-world data of nonhierarchical prescribing of biological agents supports the superiority of infliximab over adalimumab in bio-naive patients with FCD, but did not show a therapeutic difference in bio-exposed FCD. Thiopurine cotherapy was independently associated with improved biological agent persistence in FCD.