In patients with primary sclerosing cholangitis (PSC), antimicrobial therapy with oral vancomycin (OV) is increasingly used to prevent progression of the liver disease and control concomitant ulcerative colitis (UC); however, there are concerns regarding the risk of development of vancomycin-resistant enterococci (VRE). Thus, we aimed to determine the incidence of VRE in PSC-UC patients. We conducted a retrospective study of PSC-UC patients, treated with OV at the Department of Gastroenterology at the Princess Alexandra Hospital. VRE testing was performed utilizing rectal swabs. We included 7 PSC-UC patients (age 22-53 years, 2 females) treated with OV with daily dose ranging from 250 to 1500 mg. All patients were treated for at least 6 months with OV (range 9-31 months, mean 32.1 months). All patients achieved complete clinical remission of the UC, with mean reduction of fecal calprotectin by 634 μg/mg (87.3%), mean reduction in the C-reactive protein by 21.9 mg/L (74.2%), and mean reduction in the total Mayo score by 9.3 (93.3%). With regard to the liver parameters, mean improvement in alkaline phosphatase enzyme and total bilirubin was -48.7 U/L (-19.7%) and -2.7 mg/dL (-19.6%), respectively. No patient treated with OV developed VRE or reported any adverse events. This cohort study including PSC-UC patients did not provide evidence for development of VRE, while treatment with vancomycin was associated with clinical and endoscopic remission of the UC. Larger, prospective trials are required to define the efficacy and safety of antimicrobial therapy in PSC-UC, while the risk of VRE appears small.