Introduction <p>Hyperhaemolysis syndrome (HHS) is a rare, delayed type of haemolytic transfusion reaction. Early diagnosis and appropriate treatment are required to avoid adverse consequences and increased mortality. HHS has not been reported before to be associated with haemoglobin E (HbE) disease.</p> Case Presentation <p>A 37-year-old lady with a pre-existing diagnosis of HbE disease in her second pregnancy was admitted with established pre-term labour. Following a vaginal delivery, her haemoglobin levels (Hb) continued to decline from 9.4 to 5.4&#xa0;g/dL despite repeated transfusions. Her investigations showed evidence of haemolysis, positive antibody screening, and DAT with weak C3d. Phenotyping was conducted on a post-transfusion sample, revealing mixed reactions with Jk^b antisera. Consequently, a delayed haemolytic transfusion reaction due to Jk^b antibodies was suspected, for which Jk^b antigen-negative cross-match-compatible blood was transfused. However, her haemoglobin further dropped beyond the pre-transfusion value. Repeated lab investigations revealed evidence of intravascular haemolysis and poor reticulocyte response, leading to the diagnosis of hyperhaemolysis. Consequently, red-cell transfusions were withheld, with a decision to transfuse only in life-threatening situations. She was initiated on intravenous immunoglobulin and high-dose methylprednisolone, followed by oral prednisolone. Haematinics and erythropoietin were added to support erythropoiesis. The Hb began to rise to 9.8&#xa0;g/dL after 3&#xa0;weeks of immunoglobulin and steroids.</p> Conclusion <p>This case highlights the challenges in managing HHS in a pregnant woman with HbE disease. The treatment of HHS needs a multidisciplinary team approach with continuous monitoring and commencing treatment urgently to achieve a favourable outcome.</p>