Background: The PISA-II trial showed that short-term anti-TNF therapy followed by surgical closure induces radiological healing of Crohn’s perianal fistulas more frequently than anti-TNF therapy after 18 months. This study aimed to compare long-term outcomes of both treatment arms. Methods: Follow-up data were collected from patients who participated in the PISA-II trial, an international patient preference RCT. Data were collected until May 2022. Primary outcome was radiological (MRI) healing. Findings: Data were collected from 91/94 patients (36/38 anti-TNF+surgical closure, 55/56 anti-TNF). Median follow-up was 6 years (IQR 5-7). Radiological healing occurred significantly more often after anti-TNF+surgical closure (42% versus 18%; P=0·014). Clinical closure was comparable (72% versus 62%; P=0·183). Results were after re-interventions in 15% versus 53%, including (redo-)surgical closure procedures. Recurrences occurred in 0/25 patients with radiological healing versus 27/76 patients with clinical closure only, sometime during follow-up. Anti-TNF serum concentrations were higher in patients with long-term clinical closure in both groups (P=0·01). In 6/11 patients in the anti-TNF group with available serum concentrations, recurrences were diagnosed within three months of a drop under 3.5ug/ml. 36 patients stopped anti-TNF, after which 0/14 patients with radiological healing developed a recurrence and 9/22 with clinical closure only. Continence was comparable between groups, and 79% of patients indicated comparable/improved continence after treatment. Decision-regret analysis showed that all anti-TNF+surgical closure patients (strongly) agreed that surgery was the right decision versus 78% in the anti-TNF arm. All surgical closure patients would go for the same treatment again, whereas this was 89% in the anti-TNF arm. Interpretation: This study confirms that surgical closure should be considered in amenable patients with Crohn’s perianal fistulas as long-term outcomes are favourable, and that radiological healing should be the aim of treatment as recurrences only occurred in patients without radiological healing. In patients with complete MRI closure, anti-TNF could be safely stopped. Funding Information: None. Declaration of Interests: EMMP, MAJB, KLR, KATGMW, JS, MGWD, and AS have nothing to declare. GRH has received grants from Bristol Meiers Squibb, Pfizer and Takeda, has served as a consultant and/or received speaker’s fees from AbbVie, Alimentiv, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion Healthcare, Cytoki Pharma, Eli Lilly, Ferring, Galapagos, Glaxo SmithKline, Gossamer Bio, Immunic, InDex Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Takeda, Tillotts, Ventyx Biosciences. He furthermore received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer, Boehringer Ingelheim, Takeda and Abbvie, and participated on a Data Safety Monitoring Board or Advisory Board of Astrazeneca, Abbvie and Seres Health. CYP has received grants from Perspectum and Gilead; consulting fees from Shire, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Tillotts. KBG has received grants from Pfizer, Galapagos, Celltrion, consultancy fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, ImmunicTherapeutics, Janssen Pharmaceuticals, Novartis, Pfizer Inc., Samsung Bioepis and Takeda, and speaker’s honoraria from Celltrion, Ferring, Janssen Pharmaceuticals, Novartis, Pfizer Inc, Samsung Bioepis, Takeda and Tillotts. SD has received consulting fees from Abbvie, Alimentiv, Allergan, Amgen, AstraZaneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial and Vifor. He furthermore received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer and Takeda. WAB has received grants from Braun and Vifor, and has served as speaker for Takeda, Johnson and Johnson and Braun. CJB has an unrestricted grant from Boehringer Ingelheim and Roche. She has also received consultancy fees and/or speaker’s honoraria from AbbVie, MSD, Tillotts, Janssen and Takeda. Ethics Approval Statement: The PISA-II2 study received central approval from the Medical Ethical Committee at the Amsterdam University Medical Centers, location University of Amsterdam, and all other participating centres and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. For the current study, formal approval and individual patient informed consent was waived by the Medical Ethics Review Committee of the Amsterdam University Medical Centers.