This chapter focuses on the complete disruption of the main pancreatic duct with loss of continuity between the duct and the gastrointestinal tract known as disconnected pancreatic duct syndrome (DPDS), first described by Richard Kozarek in 1998. DPDS is characterized by an inability to access the tail of the pancreatic duct during endoscopic pancreatography, with imaging evidence of viable pancreatic tissue upstream of the disruption along with persistent nonhealing pancreatic fistula or fluid collection. In the setting of acute pancreatitis, DPDS presents mostly in cases with acute necrotizing pancreatitis and walled-off necrosis. Diagnosis of DPDS requires clinical awareness and suspicion. Early recognition of DPDS is paramount; theoretically, prompt and appropriate diagnosis and treatment may lead to decreased morbidity and lesser health-related costs, although some authors found that late DPDS is associated with better outcomes, shorter length of hospitalization, and lower frequency of pancreatic fistula compared with concurrent or early DPDS.