Abstract Text: Injuries from exposure to explosive blasts from the use of improvised explosive devices have increased in military settings, and in civilian populations, through acts of terrorism. Determining the neurologic effects of blast in Service Members (SMs) is challenging since it often occurs concomitant with other injuries, as well as SM’s prior exposure load that we aim to address. In recent years, investigations of the blast effect in tactical training settings have begun to address this gap in knowledge including Breachers with repeated exposures to blast. These exposures have been associated with self-reported concussion-like symptomology, transient decrements in performance, and physiological changes including elevations in blood-based neurotrauma biomarkers. We used time-series gene expression data from “breachers” exposed to controlled, low-level blast explosives during training, where blood samples were collected serially from 30 male participants (age 30.3 ± 7.5 years) at pre-blast (morning), and post-blast (afternoon) on training day 2, and follow-up on day 3 and assayed via RNA-seq. A battery of symptom data was also collected serially at each of these time points that showed elevated symptom reporting related to headache, concentration, dizziness, and slowed thinking acutely that dissipated 12hr following blast, which is in line with a constellation of symptoms typically reported following TBI. In a statistical model that examined the interaction of blast and mTBI history, we found that 33% (36/108) of genes that did show significantly altered expression following blast in the SMs who endorsed prior mTBI history are involved in inflammatory processes identified via gene set enrichment analysis including NOTCH-1, an essential regulator of microglial activation and a cell surface marker CD11b expressed in immune cells showing increase expression in SMs with mTBI history acutely following blast exposure corroborated by data from TBI experimental models. Enrichment of genes related to inflammation in SMs with prior history of mTBI is consistent with the activated immune response associated with TBI, which involves an intricate interplay between CNS-derived inflammation and systemic inflammation. These findings have a translational impact, wherein repeated exposure to low-level blast and associated sub-concussive injuries over time can augment peripheral and central inflammation contributing to functional decline.