Abstract: Spinal cord injury (SCI) induces a robust inflammatory response largely mediated by resident microglia and infiltrating macrophages across the blood-brain barrier. While these cell populations are capable of promoting repair and regenerative responses, in the days and weeks after SCI they predominately adopt pro-inflammatory profiles known to inhibit recovery and potentiate secondary injury pathways. Continued work is needed to develop clinically viable immunomodulatory therapeutics and promote pro-reparative macrophage responses. Recently we published on the therapeutic benefits of the macrolide antibiotic azithromycin (AZM), which improves locomotor and histological recovery after SCI in 3-month-old female mice (Kopper et al., 2019). Specifically, we initiated AZM beginning 30 minutes, 3, or 24 hours after injury and then daily for 7 days. AZM administration initiated at 30 minutes and 3 hours post-injury improved locomotor function as detected by an open field locomotor scale and significantly improved stepping frequency. The 24-hour time point, however, was ineffective suggesting the importance of early administration. Histologically we observed modest improvements with the 30-minute treatment time point with significantly reduced lesion length and evidence of slight increases in tissue sparing at the lesion epicenter. Previously, we observed that the same AZM dosing strategy after SCI reduces pro-inflammatory microglia and macrophage activation as determined by a diverse panel of inflammatory markers (Gensel et al., 2017). These neuroprotective findings are consistent with recent studies finding AZM to be therapeutically effective in multiple stroke models (Amantea et al., 2016b, 2019) a rat model of retinal ischemia/reperfusion injury (Zheng et al., 2007), and in a rat neonatal hypoxic-ischemic brain injury model (Barks et al., 2019). AZM is the most commonly prescribed antibiotic due in part to its safety profile and large therapeutic index (Durkin et al., 2018). Collectively, these studies highlight the potential for AZM to be developed into a safe, neuroprotective treatment for SCI and other neurological conditions. Here, we highlight additional areas of study that will facilitate the translation of AZM as a neuroprotective agent.