The efficacy of autologous bone marrow transplantation in leukemia and lymphoma may depend upon the selective elimination of malignant cells from human bone marrow in vivo and in vitro. A cyclophosphamide derivative (ASTA-Z 7654) and etoposide (VP16-213) have been tested on lymphoma and leukemia cell lines in a model that may represent a bone marrow situation in complete remission. The influence of different concentrations of normal mononuclear cells and tumor cells in this model and the activity of the two chemotherapeutic agents in the presence of bone marrow cells or peripheral blood cells were evaluated. A major inhibitory effect was observed using the two agents in combination; low doses of ASTA-Z and VP16 consecutively added to the mixture of malignant cells and normal mononuclear cells resulted in a greater elimination of tumor line cells than with ASTA-Z alone at the current 100 micrograms/ml dose. In contrast, no major toxicity on normal human bone marrow precursors was observed; the effect of treatment on hemopoietic recovery with the two agents either alone or in combination was evaluated on CFU-GM growth after long-term bone marrow cultures. Despite a profound growth inhibition at day 0, a recovery was observed in all cases after 7 or 14 days. The use of multiple chemotherapeutic agents in the treatment of bone marrow in vitro could decrease the possibility of malignant cells surviving while sparing normal bone marrow precursors.