Currently there are no effective antifibrotic therapies for liver cirrhosis, a major killer worldwide. To obtain a cellular resolution of directly-relevant pathogenesis and to inform therapeutic design, we profile the transcriptomes of over 100,000 human single cells, yielding molecular definitions for non-parenchymal cell types present in healthy and cirrhotic human liver. We uncover a novel scar-associated TREM2 + CD9 + macrophage subpopulation, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define novel ACKR1 + and PLVAP + endothelial cells which expand in cirrhosis, are topographically scar-restricted and enhance leucocyte transmigration. Multi-lineage ligand-receptor modelling of interactions between the novel scar-associated macrophages, endothelial cells and PDGFRα + collagenproducing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides the conceptual framework required to discover rational therapeutic targets in liver cirrhosis. Recent estimates suggest that 844 million people worldwide have chronic liver disease, with two million deaths per year and a rising incidence 1. Iterative liver injury secondary to any cause leads to progressive fibrosis ultimately resulting in liver cirrhosis. Importantly, the degree of liver fibrosis predicts adverse patient outcomes 2. Hence, effective antifibrotic therapies for patients with chronic liver disease are urgently required 3,4. Liver fibrosis involves a complex interplay between multiple non-parenchymal cell (NPC) lineages including immune, endothelial and mesenchymal cells spatially located within areas of scarring, termed the fibrotic niche. Despite progress in our understanding of liver fibrogenesis accrued using rodent models, there remains a significant 'translational gap' Ramachandran et al.