Specific unresponsiveness to skin allografts can be induced in ALS[anti-lymphocyte serum]-treated mice by the injection of bone marrow from the graft-donor strain. Mice bearing long-term grafts in perfect condition have evidence of cell-mediated immunity against donor antigens and also serum-blocking factors. The effect of cyclophosphamide on graft prolongation was investigated in this model. Cyclophosphamide was given before or after marrow. Cyclophosphamide given before marrow abrogated the enhancing effect of marrow, possibly due to a depletion of antibody-forming cells. Cyclophosphamide given after marrow potentiated the effect of marrow, probably due to the destruction of immunocompetent cells responding to the challenge of marrow.