Hemoglobin (Hb) disorder is a significant health problem in Southeast Asia, where HbE (β E ; codon 26 [GAG>AAG; human betaglobin gene, HBB:c.79G>A]) is a common hemoglobin variant in this region. 1,2 The interaction of HbE and other globin gene mutations can cause a nontransfusion and transfusion-dependent thalassemia syndrome. [2][3][4] By contrast, Hb Nottingham (β Nottingham ) is a rare unstable hemoglobin caused by a missense mutation at codon 98 (GTG>GGG; HBB:c.296T>G). 5 This variant was first described in 1973, 6 and only six reports have been published on Hb Nottingham worldwide. [6][7][8][9][10][11] This current report describes two Malay monozygotic twins with a rare interaction of HbE and Hb Nottingham (β E /β Nottingham ) that gave a clinical picture similar to that of transfusion-dependent HbE/beta-thalassemia. The literature reporting Hb Nottingham since 1973 was also reviewed.