INTRODUCTION: Neuroinflammation plays a critical role in tissue injury and repair after neonatal hypoxic-ischemic (HI) brain injury and varies by sex. Growth differentiation factor-15 (GDF-15) is a cytokine released by macrophages during inflammation and is upregulated after brain ischemia. We examined the impact of GDF-15 knockout (KO) on volume loss and the combined microglia/macrophage response in the Rice Vannucci model of neonatal HI injury. METHODS: Male and female wild-type (WT) Gdf15+/+, heterozygous Gdf15nuGFP-CE/+ (Het), and homozygous Gdf15nuGFP-CE/nuGFP-CE (KO) mice were bred at the University of Pittsburgh. Postnatal day 9-11 mice were randomized to sham procedure or unilateral common carotid artery ligation followed by exposure to 8% O2 for 25min. Pups were subsequently genotyped and survived for 14 days before sacrifice. Lesion volume and number of ionized calcium-binding adapter molecule 1 (Iba-1) positive cells were quantified. RESULTS: Injured male KO pups had decreased hemispheric and hippocampal lesion volume vs. injured male WT pups. Injured male Het pups demonstrated an intermediate phenotype. In males, the number of Iba-1 positive cells correlated with extent of tissue loss. In females, the extent of volume loss and Iba-1 cell counts post-injury did not vary by genotype. CONCLUSION: GDF-15 exerts a sex-dependent deleterious effect on lesion volume in a neonatal HI model. Future work should identify how GDF-15 mediates different neuroinflammatory responses between sexes, establish if brain-secreted vs. peripherally-derived GDF-15 mediates the pro-injury phenotype that was inhibited in male KOs, and test if therapeutic inhibition of GDF-15 signaling is a novel treatment for neonatal HI brain injury.