Extramedullary hematopoiesis is a characteristic feature of hepatoblastoma (HB). We investigated 15 HB to characterize intratumoral hematopoietic foci and to find clues to the pathophysiology of their formation. By conventional histology and immunohistochemistry, we found erythroblasts in all and megakaryocytes in 10 of the HB, whereas granulocyte and monocyte precursor cells could not be identified in hematopoietic foci of any tumor. Only a minority of erythropoietic cells in these foci contained fetal Hb (HbF). We recently found that HB cells produce IL-1 beta and thus stimulate stromal cells to secrete IL-6. We therefore searched for other hematopoietic cytokines in HB. Supernatants of primary HB cultures were subjected to ELISA, bioassayed, and immunoblotted. We detected erythropoietin (EPO) in 11 of 15, stem cell factor (SCF) in 7 of 11, granulocyte colony-stimulating factor (G-CSF) in 4 of 15, granulocyte/macrophage colony-stimulating factor (GM-CSF) in 6 of 15, IL-3 in 1 of 12, leukemia inhibitory factor (LIF) in 1 of 9, and macrophage colony-stimulating factor (M-CSF) in 1 of 8 conditioned media. With immunoenzymatic labeling we localized EPO and SCF to the cytoplasm of epithelial HB cells, whereas stromal cells and cells of immature fibrous tissue of mixed HB expressed SCF, G-CSF, GM-CSF, LIF, and M-CSF. EPO and SCF could also be detected in extracts of epithelial HB cells. We conclude that, in HB, erythropoiesis and megakaryopoiesis but not the granulocyte-macrophage lineage is induced by fetal and embryonal tumor cells in cooperation with stromal cells by locally secreted cytokines.