INTRODUCTION: Vedolizumab is a commonly prescribed biologic agent due to its safety profile and clinical efficacy. Severe infusion-related reactions are exceedingly rare, with no previously documented cases of anaphylaxis to vedolizumab infusion following a drug holiday. CASE PRESENTATION: We report the case of a 65-year-old male with ulcerative colitis who had a severe anaphylactic reaction to the first re-induction infusion of vedolizumab following a 30-month drug holiday. No pre-infusion prophylactic medication was administered. Upon commencement of the infusion, the patient developed anaphylactic symptoms including airway compromise that required intensive care unit admission and treatment with an adrenaline infusion. CONCLUSION: Anaphylactic reactions to vedolizumab after a drug holiday can occur. As is done for infliximab, we recommend administration of an antipyretic, antihistamine, and corticosteroid prior to vedolizumab re-induction infusions when it is given after a drug holiday.