Hormone replacement therapy increases risk of deep venous thrombosis (DVT) mainly in the extremities and lungs. There are reports of mesenteric ischemia secondary to oral contraceptive pills but no reports on hormone replacement therapy and mesenteric thrombosis. The authors present a case of a 44-year-old obese (BMI 32) woman, on long-term hormone replacement therapy, presented with thrombosis of portal, splenic and superior mesenteric veins. She underwent surgical resection of ischemic bowel and planned re-look laparotomies with further resections and jejuno-ileal anastomosis at final laparotomy. Thorough haematological investigations were normal. The authors conclude that hormone replacement therapy in obese patients with no other risk factors can cause a catastrophic mesenteric thrombosis. Aggressive surgical resection with re-look laparotomies and further resections can be lifesaving.