Chronic intestinal pseudo-obstruction is an extremely rare disease characterized by repeated episodes of intestinal obstruction, with radiological imaging showing a dilated intestine with air/fluid levels in the absence of mechanical occlusive lesions. A 61-year-old woman with lifelong CIPO and megaduodenum underwent multiple surgeries: jejunal resection, volvulus derotations, and gastric bypass with gastrojejunal anastomosis. Absent contractility was found on esophageal manometry. Due to a family history of esophageal adenocarcinoma, she underwent upper GI endoscopy, revealing distal erosions and a low-grade dysplastic area that was resected. Follow-up endoscopy showed persistent severe erosive esophagitis, despite high-dose PPI therapy, and a massively dilated duodenum. This case highlights the coexistence of megaduodenum and refractory esophagitis in CIPO, emphasizing the need for individualized management.