We studied hemopoiesis in mice deficient by the tumor necrosis factor gene. The total number of cells in long-term bone marrow cultures from these mice 2-fold surpassed that in wild-type and tumor necrosis factor p55 receptor-deficient animals. Increased cell production was related to the absence of tumor necrosis factor expression by hemopoietic precursors. The total cell production by explanted hemopoietic cells from tumor necrosis factor-deficient mice did not depend on the genotype of irradiated stromal sublayer in long-term cell cultures from wild-type mice and animals deficient by tumor necrosis factor or p55 receptor. These results suggest that tumor necrosis factor, but not its p55 receptor, is involved in transduction of signals regulating production of cultured cells. Tumor necrosis factor probably regulates hemopoiesis in long-term bone marrow cultures by initiating apoptosis of hemopoietic cells or inhibiting cell proliferation. Increased cell production probably attests to the absence of one or both effects.