The benefit of oxygen (O2) therapy in non-hypoxic sickle cell patients in painful crisis is uncertain. We report a case of a non-hypoxic sickle cell patient in painful crisis who developed marrow red cell hypoplasia requiring transfusion support after O2 therapy. The uncertain benefits of O2 use in such cases must be weighed against the serious and underrecognized risks of transfusion. In patients who develop O2-induced marrow red cell hypoplasia, cessation of O2 therapy may reverse the anemia and obviate the need for transfusion.