In thalassemia major (TM), without iron chelation therapy, iron-mediated free radical damage causes liver, endocrine, and myocardial toxicities. Deferoxamine has universally been the standard therapeutic option for iron chelation therapy; however, its usage is troublesome, leading to suboptimal patient compliance. In order to maximize the effectiveness of iron chelation therapy, oral iron chelators deferiprone and deferasirox constitute an important development, offering a potential to improve compliance. Although both oral drugs are effective, they have differences including different pharmacokinetics and side-effect profiles. Our retrospective evaluation of TM patients using oral chelators showed that oral chelators are effective in reducing iron overload regarding ferritin level and partially in cardiac T2* value. However, in our study side effects and discontinuation rates were unexpectedly high and close follow-up of TM patients using oral chelators should be carefully done. The variability in rate of side effects and drug discontinuation in spelenectomized patients using oral chelators suggests that spleen may have a role in pharmacokinetics of these drugs, as well.