Patients require immunosuppression after heart transplantation. Conditions such as Crohn's disease can impact tacrolimus absorption and pharmacokinetics. Subtherapeutic tacrolimus levels can lead to rejection and development of donor-specific antibodies (DSA), resulting in the development of cardiac allograft vasculopathy. We present a boy who underwent an ABO blood groupincompatible heart transplant at 10 months of age, and developed diarrhea and subtherapeutic tacrolimus levels with subsequent development of de novo DSA, and then acute cellular and antibody-mediated rejection. He was diagnosed with Crohn's disease, which required vedolizumab for control. Despite aggressive reduction of his DSA, he developed rapidly progressive cardiac allograft vasculopathy and required retransplant, with a high prevalence of plasma cells in the explanted heart. Donor-directed blood group antibodies remained negative. This case demonstrates the importance of early consideration of inflammatory bowel disease for patients with diarrhea and subtherapeutic tacrolimus levels, as prompt diagnosis and treatment may prevent secondary graft injury.