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Vedolizumab-associated adverse effects, including infusion reactions, are generally uncommon. Less than 5% of patients experience an infusion-related reaction. We report a 67-year-old male with ulcerative colitis under prolonged maintenance therapy who presented with recurring chest pain occurring immediately after consecutive vedolizumab infusions. Medical workup of possible etiologies for chest pain were investigated and excluded. Vedolizumab drug trough levels were negative, accompanied by high detectable levels of anti-vedolizumab antibodies. These findings demonstrate an uncommon case of an infusion reaction to vedolizumab infusion.