Total pancreatectomy with islet autotransplantation (TPIAT) offers unique advantages over standard total pancreatectomy, retaining some endogenous insulin production to improve quality of life. However, TPIAT also carries a risk of postoperative complications. Beyond endocrine and exocrine insufficiency, patients may be prone to gastrointestinal dysmotility syndromes (e.g., obstipation, gastroparesis). Furthermore, susceptibility to infections, both intra-abdominal and systemic, can increase due to anatomic alterations and changes in immune regulation, especially after splenectomy. Late postoperative issues include nutritional deficiencies, bone density loss, and psychological challenges, emphasizing the value of a comprehensive, multidisciplinary care model with close endocrine follow-up, thorough nutritional support, and regular screening for treatable complications. Moreover, recognizing risk factors, implementing preventive strategies, and standardizing treatment protocols remain priorities for centers offering TPIAT. In this chapter, we provide an overview of the most significant medical complications that can arise after TPIAT and outline evidence-based management approaches based on the latest research and our own clinical experience.