Introduction: Neonatal hypoxia-ischemia (HI) is a leading cause of mortality and chronic disability. Hypothermia (HT) is the gold standard for the treatment of term babies; however, its neuroprotective effects are limited. Lactoferrin (LF) is the major whey protein in milk presenting iron-binding, anti-inflammatory and anti-apoptotic against HI damage. We hypothesize that combining oral administration of LF to the dams enhances the neuroprotection caused by HT following experimental HI. Methods: Pregnant Wistar rats were fed with bovine LF-supplemented diet (1mg/kg) or Control diet from P6 to P27. At P7, male and female pups had the right common carotid artery occluded followed by hypoxia (8% O2 for 60’) (HI). Immediately after hypoxia, hypothermia (target temperature of 32.5-33.5°C) was performed (5h duration) using Criticool®. Animals were divided according to: diet as Control (CT) or Lactoferrin-enriched (LF); surgical sham (SH) or lesion (HI) and normothermic (NT) or hypothermia-treated (HT). At P8 (24h after HI) and P27, lesion volume was assessed using hyperintense T2W signal acquired in a 9.4T scanner. From P23, animals were tested for motor function and cognition. Results: We observed early additive effects of LF diet and HT over brain lesion at P8. However, no synergistic effects between LF and HT were observed in the cylinder test at P27. Our preliminary data shows additive effects between therapies over early brain damage. Ongoing analysis aims further reveal if there is an interaction between HT and LF over cognition and long-term tissue damage following neonatal brain hypoxia-ischemia.