This study examined the theoretical availability of compatible unrelated umbilical cord blood (UCB) units for hematopoietic stem cell transplantation (HSCT) of children with sickle cell disease (SCD), matched for DRB1 at high resolution. UCB units registered via Bone Marrow Donors Worldwide were matched with patients who had been previously typed for possible HSCT. Suitable matching was determined after typing at antigen level at A and B loci and allele-level typing at DRB1. Forty patients met criteria for analysis. All matched at four of six loci with at least two UCB units, and 50% (n = 20) matched at five of six loci with at least one unit. In patients matched at four loci or more, significantly more units per patient (median 19 vs. 2 units; P = 0.03) at higher cell dose (median 205 vs. 113 best nucleated cell dose per unit; P < 0.01) were identified compared with patients matched at five loci or more. Hypothetically, at a dose of at least 5 x 10 nucleated cells/kg, 54% of patients weighing 40 kg would match with units at four or more of six loci and 5% at five or more of six loci. This study suggests that cord blood units matching at four or more of six HLA loci at acceptable cell doses can be identified for a majority of children with SCD weighing 40 kg or less. Availability of units matched at five or more of six HLA loci was more limited. Defining procedure-related risks and benefits remains a challenge.