Orally administered interleukin (IL)-6 has been shown to be of benefit in eliminating Campylobacter infection and in preventing sepsis following hemorrhage. In related experiments, it was seen that proliferating cells were found in the spleens of untreated mice given IL-6 by oral gavage. Injection of the DNA label, BrdU, showed that significant proliferation began at 4 h and peaked at 24 h in the splenic red pulp of animals given oral IL-6. Mice given saline showed no increase in splenic BrdU uptake. Histological analysis suggested a hematopoietic lineage for these cells. Clonogenic assays performed on spleen cells taken from mice given oral IL-6 revealed that increased granulocyte-macrophage colony forming units (GM-CFU) were present at 24 h post-IL-6 administration. No increase in GM colonies occurred in mice fed IL-3, granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage (GM)-CSF. RT-PCR analysis of intestinal mRNA from treated mice revealed that GM-CSF mRNA was elevated at 4 h after oral IL-6 administration, but not in mice fed other cytokines. It is suggested that oral administration of IL-6 induces both proliferation and a brief elevation of GM-CFU in the hematopoietic spleens of mice. This increase appears to be the result of increased GM-CSF mRNA production in the intestines of mice fed IL-6.