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A middle-aged woman with a 6-year history of stable inflammatory bowel disease (IBD) presented with progressively worsening abdominal pain, increased stool frequency and rectal bleeding. Colonoscopy revealed patchy inflammation in the descending colon, and PCR testing detected 6961 copies/mL of Epstein-Barr virus (EBV) DNA in inflamed tissue. Initial treatment with steroids and azathioprine led to partial improvement, but azathioprine had to be discontinued due to significant adverse effects. A follow-up colonoscopy demonstrated persistent inflammation, despite declining EBV DNA levels in inflamed tissue prompting the initiation of infliximab with initial improvement. However, symptoms recurred within months and secondary infliximab failure was confirmed on therapeutic drug monitoring. The patient was subsequently switched to vedolizumab and has since shown good clinical response. This case underscores the potential utility of routine EBV viral load monitoring in patients with refractory IBD and highlights the complexities of managing EBV-associated colitis with standard immunosuppression.