The in vivo thrombopoietic activity of polyethylene glycol-modified interleukin-6 (MPEG-IL-6), in which 54% of the 14 lysine amino groups of IL-6 were coupled with PEG, was compared to that of native IL-6. Native IL-6 and MPEG-IL-6, which showed about 51 % of the specific bioactivity of native IL-6, were administered subcutaneously to mice every 2 days for 7 days. Native IL-6 increased not only the peripheral platelet count, but also the plasma-IgG1 level in a dose-dependent manner. MPEG-IL-6 showed about 500 times higher thrombopojetic potency than native IL-6. Further, in comparison to native IL-6, MPEG-IL-6 did not enhance IgG1 production as much as it enhanced platelet production. MPEG-IL-6 significantly stimulated platelet recovery in mice treated with 5-fluorouracil, whereas the administration of native IL-6 had a negligible effect. The plasma half-life of MPEG-IL-6 was about 100-fold longer than that of native IL-6. The decrease in the plasma clearance of MPEG-IL-6 was thought to be due, in part, to the shielding of the proteolytic sites in the IL-6 molecule by the PEG chain. The uptake of IL-6 by the reticuloendothelial system, such as the liver and spleen, was markedly limited by PEGylation. The PEGylation of IL-6 markedly enhanced the blood-residency of IL-6, resulting in effective augmentation of its thrombopoietic activity and a marked decrease in its side-effects. These findings suggest that MPEG-IL-6 may be a potential candidate for thrombopoietic agent.