Introduction: It is known that the tolerance for return to normal neuromuscular function in tissue exposed to ischemia with concomitant hemorrhagic shock is significantly reduced compared to ischemia alone (Hancock et al., 2011). With an increased incidence of explosive related injuries in military casualties, the ischemic tolerance following blast injury with or without hemorrhagic shock may also be altered. A possible mechanism of altered tolerance is via damage to the endothelium. Endothelial integrity may influence clinical outcomes locally and systemically. Aim: This study determined whether blast injury alone caused activation of, or damage to, the endothelium and whether this was correlated with the level of blast load. Methods: Experiments were performed under the auspices of Animals (Scientific Procedures) Act 1986 and thus had undergone local Ethical Review. Groups of terminally anaesthetised female New Zealand White rabbits were exposed to 4 different levels of blast over the gastrocnemius muscle via a compressed air device. Arterial blood samples were taken pre-injury and 1, 6 and 11hr post-injury to determine levels of circulating endothelial cells (CECs) using CD146-based immunomagnetic separation. 12 hours post injury animals were culled with an overdose of anaesthetic and tissue removed for histological and gene expression analysis. The incidence of haemorrhage, oedema and inflammatory cell infiltration were subjectively scored. mRNA levels of markers associated with the activation of the endothelium were measured using qRT-PCR with multiple reference gene normalisation. Differences in CECs between groups were assessed with 2-way ANOVA (p<0.05 and power = 0.8). Histology scores were assessed using a Cuzicks trend test (p<0.05). qRT-PCR results were expressed as calibrated normalised relative quantities (CNRQ), transformed and assessed using one-way ANOVA (p<0.05). Results: At 6 hr post-injury, the number of CECs in blood was significantly higher in the high blast group versus no blast group (p<0.05). There was a significant trend (p<0.0001) in increasing scores for oedema, haemorrhage and cell infiltrate with increased blast load. Expression of a variety of endothelial activation markers were significantly increased in the high blast versus no blast group including E-selectin, TNFα, HIF-1α and Thrombomodulin. Conclusions: This study demonstrates that blast injury causes activation and damage to the endothelium and surrounding muscle tissue and that this is dependent on blast load. This has the potential to impact on limb salvage strategies and requires further investigation to determine the implications for casualties injured in an explosion. Understanding the mechanism of damage may also identify possible mitigation strategies.