Interleukin-6 (IL-6) is a pleiotropic cytokine that enhances the maturation of megakaryocytes. In mice, in vivo treatment with IL-6 results in elevated platelet counts both in untreated animals and after myelosuppressive therapy. In this study, we assessed the effect of continuous infusion of IL-6 in sublethally irradiated (7 Gy) mice on peripheral blood cell counts and progenitor cells in bone marrow and spleen. Female Swiss mice were treated by continuous infusion with 1 or 10 micrograms IL-6 per day for 7 or 14 days. Continuous infusion of IL-6 for 7 days resulted in elevated levels of circulating IL-6 (mean: 1872 pg/mL vs. 100 pg/mL for phosphate-buffered saline [PBS]-treated controls) and in an accelerated reconstitution of platelets starting at day 12 after irradiation. In IL-6-treated animals, the 50% pretreatment platelet count was reached on day 15 vs. day 21 for irradiated controls receiving no IL-6. Treatment with IL-6 for 14 days resulted in a further increase in platelet counts, exceeding the pretreatment counts. The number of colony-forming units-megakaryocyte (CFU-Mk) was significantly elevated from day 6 to 18 in the spleen but not in bone marrow. To assess the contribution of extramedullary megakaryocytopoiesis in the spleen to IL-6-induced platelet recovery, IL-6 was also administered to splenectomized mice. The stimulatory effect of IL-6 on platelet recovery was preserved in these animals, indicating that megakaryocytopoiesis in the spleen did not contribute to the accelerated recovery of platelets. The neutrophil counts were elevated during IL-6 treatment and became similar to controls after cessation of therapy, whereas the numbers of colony-forming units-granulocyte/macrophage (CFU-GM) in the bone marrow were elevated from day 9 to 24 in all animals treated with 10 micrograms IL-6 per day. In conclusion, continuous infusion of IL-6 stimulates platelet recovery after irradiation without increasing the number of CFU-Mk and conversely stimulates the proliferation of myeloid progenitor cells without an effect on neutrophil reconstitution.