Red cell allo-antibodies directed against the Diego (Di) blood group antigen have rarely been reported to cause a haemolytic reaction against transfusion or haemolytic disease of the newborn. The frequency of the Di(a+) phenotype among the Hong Kong Chinese population is estimated to be 4.4%. We report on a case of severe haemolytic disease of the newborn due to anti-Di(a) antibody—the first local case to the best of our knowledge. Rare but clinically significant antibodies targeting red blood cells have to be considered in the investigation of haemolytic disease of the newborn when common underlying factors have been eliminated.