Disruption of collagen X function in hypertrophic cartilage undergoing endochondral ossification was previously linked to altered hematopoiesis in collagen X transgenic (Tg) and null (KO) mice (Jacenko et al.,  Am J Pathol 160:2019–2034). Mice displayed altered growth plates, diminished trabecular bone, and marrow hypoplasia with an aberrant lymphocyte profile throughout life. This study identifies altered B220+, CD4+, and CD8+ lymphocyte numbers, as well as CD4+/fox3P+ T regulatory cells in the collagen X mice. Additionally, diminished in vitro splenocyte responses to mitogens and an inability of mice to survive a challenge with Toxoplasma gondii, confirm impaired immune responses. In concert, ELISA and protein arrays identify aberrant levels of inflammatory, chemo-attractant, and matrix binding cytokines in collagen X mouse sera. These data link the disruption of collagen X function in the chondro-osseous junction to an altered hematopoietic stem cell niche in the marrow, resulting in impaired immune function. Developmental Dynamics 237:2693–2704, 2008. © 2008 Wiley-Liss, Inc.