INTRODUCTION: Intraventricular hemorrhage of prematurity (IVH) interrupts normal white matter development. During normal brain development, microglia play an important role in myelination by producing insulin-like growth factor 1 (IGF-1) which is necessary for oligodendrocyte progenitor cells (OPCs) to mature into myelinating oligodendrocytes. IGF-1 is produced by a subpopulation of microglia that express the antigen CD11c, and these microglia are enriched during early brain development. METHODS: A cell culture system of isolated microglia was used for in vitro studies. A rat model of neonatal IVH was used for in vivo studies. Magnetic bead sorting was used to isolate CD11c+ microglia. Real-time PCR was used to quantify IGF-1 expression. ELISA was used to measure IGF-1 and cytokine production. Immunohistochemistry was used to quantify white matter and label OPCs, microglia, and CD11c. RESULTS: Hemoglobin induced a greater degree of TNFa production compared to an equivalent dose of whole blood. in vitro, hemoglobin reduced the percentage of microglia that expressed CD11c, and reduced the IGF-1production measured by ELISA. In an animal model of neonatal IVH, where hemoglobin injection reduces white matter development but not OPC survival, CD11c+ cells decreased their IGF-1 production as measured by real-time PCR. CONCLUSION: Hemoglobin is a potent pro-inflammatory stimulus for microglia in the developing brain. Hemoglobin induces classically proinflammatory microglial activation, with production of cytokines and reduction of IGF-1 production. CD11c+ microglia, the cells that provide the IGF-1 critical for myelination, reduce IGF-1 production in vivo when exposed to hemoglobin. This loss of microglial IGF-1 may be the reason OPCs fail to mature and myelinate effectively. Replacing IGF-1 maybe a therapeutic strategy for neonatal IVH.