Prior to initiating gene therapy trials for sickle cell disease (SCD), methods to collect sufficient numbers of hematopoietic stem and progenitor cells will need to be developed. Bone marrow harvest entails significant morbidity that could be severe in patients with SCD. In addition, an ability to perform repeated stem cell collections so that several transfers of genetically modified cells could be attempted would be advantageous. In other settings, apheresis collection of mobilized blood stem cells has become the preferred source of stem cells for transplantation. Unfortunately, patients with SCD do not tolerate granulocyte-colony stimulating factor and therefore cannot be mobilized using these conventional methods. In this pilot study, we investigated whether withdrawal of hydroxyurea therapy results in an increase in circulating numbers of CD34+ cells and hematopoietic progenitors. In addition, we performed leukapheresis in one patient with severe SCD in an attempt to determine whether blood stem cell collection can be performed safely in patients who would be candidates for SC gene therapy trials. Our results highlight some of the potential difficulties in initiating gene therapy clinical trials for sickle cell disease.