Our preliminary data indicate that rosiglitazone may be myeloprotective. We investigated whether it can modify bone marrow recovery. Five-day pre-treatment with rosiglitazone significantly accelerated recovery of 5-fluorouracil-damaged bone marrow in mice. Frequency and femoral content of granulocyte-macrophage progenitors reached mean baseline faster in pre-treated groups than in 5-fluorouracil-treated controls. Consequently, neutropenia was milder. Five-day insulin pre-treatment had similar effects in vivo. Insulin supports in vitro hematopoiesis. The observed myeloprotection demonstrated the importance of insulin in vivo. Clinical use of insulin to moderate myelotoxicity is impractical but rosiglitazone, an insulin sensitizer, could offer hope. Although rosiglitazone tends to increase plasma insulin levels, the significant myeloprotection was partly due to direct effects on progenitors. In vitro rosiglitazone enhanced the survival of both murine progenitor and human mobilized blood stem cells in the presence of 5-fluorouracil, the effect of which was neutralized by a peroxisome-proliferator-activated receptor-gamma antagonist.