b-thalassemia is a worldwide distributed monogenic red cell disorder, characterized by the absence or reduced b-globin chainsynthesis. Despite the extensive knowledge of the molecular defects causing b-thalassemia, less is known about the mechanismsresponsible for the associated ineffective erythropoiesis and reduced red cell survival, which sustain anemia of b-thalassemia.Theunbalance of alpha-gamma chain and the presence of pathological free iron promote a severe red cell membrane oxidative stress,which results in abnormal b-thalassemic red cell features.These cells are precociously removed by themacrophage systemthroughtwomechanisms: the removal of phosphatidylserine positive cells and through the natural occurring antibody produced against theabnormally clustered membrane protein band 3. In the present review we will discuss the changes in b-thalassemic red cell homeostasisrelated to the oxidative stress and its connection with production of microparticles and with malaria infection.The reactiveoxygen species (ROS) are also involved in ineffective erythropoiesis of b-thalassemia through still partially known pathways. Novelcytoprotective systems suchasASHP, eIF2, and peroxiredoxin-2 have been suggested to be important againstROS in b-thalassemicerythropoiesis. Finally, we will discuss the results of the major in vitro and in vivo studies with antioxidants in b-thalassemia.