AimsThe aims of this study, using a porcine model of multiple trauma, were to investigate the expression of microRNAs at the fracture site, in the fracture haematoma (fxH) and in the fractured bone, compared with a remote unfractured long bone, to characterize the patterns of expression of circulating microRNAs in plasma, and identify and validate messenger RNA (mRNA) targets of the microRNAs.MethodsTwo multiple trauma treatment strategies were compared: early total care (ETC) and damage control orthopaedics (DCO). For this study, fxH, fractured bone, unfractured control bone, plasma, lung, and liver samples were harvested. MicroRNAs were analyzed using quantitative real-time polymerase chain reaction arrays, and the identified mRNA targets were validated in vivo in the bone, fxH, lung, and liver tissue.ResultsMicroRNA expression was associated with the trauma treatment strategy and differed depending on the type of sample. In the ETC group, a more advanced fracture healing response, as reflected by the expression of osteogenic microRNAs, was seen compared with the DCO group. DCO treatment resulted in a more balanced immune response in the systemic circulation as represented by significant upregulations of several anti-inflammatory microRNAs. The in vivo validation of the abundance of putative mRNA targets reflected the levels of microRNAs which were identified.ConclusionLocal and systemic microRNA patterns of expression were identified, specific for the treatment strategy in multiple trauma, which corresponded with the expression of mRNA at the fracture site and in target organs. These findings match clinical observations and offer insights into the cellular communication which may underlie the effects of using different surgical strategies in patients with multiple trauma, both locally and systemically. We also identified a systemic involvement of microRNAs in multiple trauma which may include distant cellular communication between injured tissues. Further research may further describe the temporospatial role of circulating microRNAs after multiple trauma, their potential role in communication between organs, and prospective therapeutic applications.Cite this article: Bone Joint J 2025;107-B(2):193–203.