Occlusion of the marrow cavity by excessive bone formation in young osteopetrotic (op/op) mice results in a significant reduction in the space available for hematopoiesis. At this time, splenomegaly is evident, and the spleen is a site of significant extramedullary hematopoiesis. In vitro clonal assays of spleen cell suspensions in young op/op mice demonstrated a 22-fold elevation in the content of high proliferative potential colony-forming cells (HPP-CFC) (4 weeks of age) and a 14-fold elevation in the content of committed progenitors responsive to colony-stimulating factor-1 (CSF-1) (6 weeks of age). Flow-cytometric analysis also demonstrated a shift in the myeloid:lymphoid cell ratio in the spleens of young op/op mice, with a 35% reduction in the number of B220+ cells, and a two-fold increase in myeloid cells expressing the hematopoietic cell surface lineage antigens Mac-1 and Gr-1. However, the hematopoietic deficiencies of op/op mice are not permanent. An age-related progressive remodeling of the bone marrow cavity results in the correction of bone marrow parameters by 22 weeks of age. This correction in marrow hematopoietic activity is accompanied by a resolution of the splenomegaly, a progressive decrease in splenic hematopoietic activity at both the primitive and committed progenitor cell levels, and a correction of the lymphoid:myeloid cell ratio. Negative immunomagnetic selection of splenic hematopoietic progenitor cells from op/op and control littermate mice, followed by analysis of their expansion in liquid culture, demonstrated that primitive hematopoietic progenitor cells of high proliferative potential continued to reside in the spleen of old op/op mice. The response of these mice to a 5-fluorouracil (5-FU) cytotoxic challenge suggested that this pool of primitive progenitor cells acted as a hematopoietic reserve capable of rapidly responding to hematopoietic perturbation.