Refractory peptic ulcer disease (PUD) manifests as either hemorrhagic complications (persistent or recurrent bleeding) or gastrointestinal (GI) complications (perforation, stricture, obstruction). Treatment strategies for hemorrhagic complications include Endoscopic therapy, surgery, and transcatheter angiographic embolization. Treatment strategies for GI complications include endoscopic dilation for stricture and surgery for perforation and obstruction. Potential etiologies of persistent or worsening PUD must be considered in these cases and include the following: patient risk factors and noncompliance, persistent Helicobacter pylori infection, and non–H pylori–related infection, related to underlying idiopathic gastric hypersecretion or Zollinger-Ellison syndrome and gastrinoma. An appropriate and meticulous diagnostic work-up for refractory PUD is mandatory.