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The relationship between placental pathology and the maternal syndrome of preeclampsia is incompletely characterised. Mismatch between placental nutrient supply and fetal demand induces stress in the syncytiotrophoblast, the layer of placenta in direct contact with maternal blood. Such stress not only increases the release of extracellular vesicles into the maternal circulation, but also changes their content. We discovered that 5’-tRNA fragments (5’-tRF) constitute the majority of small RNA in these vesicles. We characterised 5’-tRF profiles in perfusion-derived syncytiotrophoblast vesicles in early-onset preeclampsia (<34 weeks), finding >900 differentially expressed fragments compared to normal pregnancy. We detected preeclampsia-dysregulated 5’-tRF in peripheral plasma using qPCR, where we identified a pregnancy-specific, placentally-derived load. These 5’-tRF induced sterile inflammation in macrophages but not monocytes. This resulted in indirect activation of endothelial cells. Our findings suggest syncytiotrophoblast-derived 5’-tRF may contribute to distant vascular inflammation, previously described in preeclampsia. This is the first demonstration of endocrine actions of vesicle-bound 5’-tRF, which may have relevance to maternal adaptation in healthy pregnancy as well as other pregnancy-related diseases.