The effects of systemic graft-versus-host (GVH) reactions on B lymphocyte production in the bone marrow of mice were examined by quantitating populations of pre-B cells and B lymphocytes. Acute and chronic GVH reactions were induced by injecting A strain lymphoid cells into either (C57BL/6 X A) F1 or (CBA X A) F1 mice, respectively. Control groups of F1 hybrid mice were given syngeneic lymphoid cells. By double immunofluorescence labeling for cytoplasmic mu heavy chains of IgM (c mu) and for surface mu (s mu) the absolute numbers of pre-B cells (c mu + s mu-) and B lymphocytes (s mu +) in the bone marrow and spleen were determined. During acute GVH reactions, the pre-B cells and B lymphocytes in the bone marrow fell rapidly in numbers and were almost absent from 16 days until the end of the 30-day experimental period. In the spleen, the number of B lymphocytes remained normal for 8 days, then fell to less than 2% of control values from 16 days onward. A similar initial decline in pre-B cells and B lymphocytes occurred during chronic GVH reactions. In long-term survivors of GVH reactions, pre-B cells and B lymphocytes began to reappear after 40 days and maintained normal numbers from 100 to 150 days. The antibody response of spleen cells to sheep red blood cells was lost during GVH reactions. However, this occurred even before B lymphocytes were eliminated and the response remained subnormal after B lymphocyte numbers had recovered. The results demonstrate that systemic GVH reactions markedly depress the normally active genesis of primary B lymphocytes in the bone marrow of the host, accounting in part for the associated state of humoral immunodeficiency.