X-linked severe combined immunodeficiency (X-SCID) is the most common form of human SCID and is caused by mutations in the common gamma chain (gammac), a shared component of the interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. BMT for human X-SCID results in engraftment of donor T-cells and reconstitution of normal T-cell function but engraftment of few, if any, donor B-cells and poor reconstitution of humoral immune function. Canine X-SCID is also caused by mutations in the yc and has an immunological phenotype identical to that of human X-SCID. We have previously reported that transplantation of nonconditioned X-SCID dogs with unfractionated histocompatible bone marrow results in engraftment of both donor B- and T-cells and reconstitution of normal T-cell and humoral immune function. In this study, we assessed the ability of purified canine CD34+ bone marrow cells to reconstitute lymphoid populations after histocompatible BMT in 6 nonablated X-SCID dogs. All dogs showed engraftment of donor T-cells, with T-cell regeneration occurring through a thymic-dependent pathway, and had reconstituted normal T-cell function. In contrast to our previous studies, only 3 dogs had engraftment of donor B-cells and reconstituted normal antigen-specific B-cell function post-BMT. The variable donor B-cell engraftment and reconstitution of normal humoral immune function observed in this study are similar to the outcomes observed in the majority of human X-SCID patients following BMT. This study demonstrates that canine CD34+ cells contain progenitors capable of immune reconstitution and is the first study to document the ability of CD34+ bone marrow cells to reconstitute normal B- and T-cell function in a nonablated large-animal model of BMT. This study also demonstrates that the quality of immune reconstitution following CD34+ BMT may be dosage dependent Thus canine X-SCID provides a large-animal preclinical model that can be used not only to determine the optimal conditions for both donor B- and T-cell engraftment following CD34 BMT, but also to develop and evaluate strategies for gene therapy protocols that target CD34 cells.