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Summary: Background: Data on oral vancomycin for primary sclerosing cholangitis (PSC)‐associated inflammatory bowel disease (IBD) are limited. Aims: Using data from the Paediatric PSC Consortium, to examine the effect of vancomycin on IBD activity. Methods: In this retrospective multi‐centre cohort study, we matched vancomycin‐treated and untreated patients (1:3) based on IBD duration at the time of primary outcome assessment. The primary outcome was Physician Global Assessment (PGA) of IBD clinical activity after 1 year (±6 months) of vancomycin. We used generalised estimating equations (GEE) to examine the association between vancomycin and PGA remission, adjusting for IBD type, severity and medication exposures. Secondary outcomes included serum labs and endoscopic remission (global rating of no activity) among those with available data and also analysed with GEE. Results: 113 PSC‐IBD patients received vancomycin (median age 12.7 years, 63% male). The matched cohort included 70 vancomycin‐treated and 210 untreated patients. Vancomycin was associated with greater odds of IBD clinical remission (odds ratio [OR] 3.52, 95% CI 1.97–6.31; adjusted OR [aOR] 5.24, 95% CI 2.68–10.22). Benefit was maintained in sensitivity analyses restricted to non‐transplanted patients and those with baseline moderate–severe PGA. Vancomycin was associated with increased odds of endoscopic remission (aOR 2.76, 95% CI 1.002–7.62; N = 101 with data), and with lower CRP (p = 0.03) and higher haemoglobin and albumin (both p < 0.01). Conclusion: Vancomycin was associated with greater odds of IBD clinical and endoscopic remission. Additional, preferably randomised, controlled studies are needed to characterise efficacy using objective markers of mucosal inflammation, and to examine safety and define optimal dosing. [ABSTRACT FROM AUTHOR]