Sickle cell disease can be corrected by hematopoietic cell transplantation but success is limited by low availability of matched related/unrelated donors and comorbidities leading to the increased transplant-related morbidity/mortality. There is a need for expanded donor pools and reduced intensity regimens. We describe a case of a second unrelated cord blood transplant after a novel preparative regimen in a child with sickle cell disease related stroke and liver fibrosis. Hydroxyurea, rituximab, and alemtuzumab were followed by thiotepa and low dose total body irradiation before unrelated cord blood transplant. Rapid full donor chimerism and improved performance status was achieved and sustained over 2 years after transplant.