INTRODUCTION: Liver sinusoidal endothelial cells (LSEC) due to their extraordinary scavenger activity are playing a pivotal role in blood-borne virus clearance. LSEC account for the 20% of hepatic cells and are unique organresident cell population with diverse functions, including degradation of bacterial by-products, antigen presentation and induction of tolerance. While these processes are particularly relevant to HCV infection, the role of LSEC in chronic hepatitis C is not defined. ----- MATERIALS AND METHODS: Aim of this study was to apply systems biology approaches to evaluate the role of LSEC in HCV infection. Poly(A) RNAs from HCV, MOCK or LPS treated primary LSEC cultures were analyzed by RNAsequencing (Illumina) to identify differentially expressed genes (DEG) and biological pathways. Cell transcriptomes were compared to similar analysis with mild (no fibrosis) and severe (cirrhosis) hepatitis C livers, hepatoma and Kupffer cells. ----- RESULTS: Following exposure LSEC internalized HCV, but failed to support HCV replication. LSEC overall displayed 754, 245 and 2543 DEG at 8, 24 and 48h after HCV exposure, respectively. While LPS stimulation triggered exceptionally potent activation, HCV in general induced a downregulation of inflammatory signals. The key innate immune response pathways were significantly downregulated (RIG-I and TLR-signaling pathways), which manifested by the diminished PRR transcripts expression with subsequent tuning down of the expression of the genes encoding for adaptor proteins, JAK-STAT, NF-κB and IRF signaling cascades resulting in the reduced expression of cytokine genes and reflecting in the deficiencies of innate immune response. Molecular mechanisms of these processes involve: upregulation of transcriptional factors essential for the induction of antiinflammatory state (such as MAFB, NUPR1, IL33, KLF15, CEBPD) and downregulation of those shown to promote inflammatory responses (ETV1, MITH, HDAC9, EGR3, IRF6). Meanwhile, a plethora of immunomodulatory genes were significantly upregulated (ACP5, A2M, C1QTNF1, NT5E, SERPING1, BMPER) that might extend to surrounding cells and attenuate liver inflammation. Gene pathway analysis further highlighted enriched KEGG pathways related to cell scavenger functions (e.g. Fc gamma R-mediated phagocytosis, Cell adhesion molecules, Focal adhesion, Leukocyte transendothelial migration, Axon guidance), innate immune responses and cancer development (Pathways in cancer, Apoptosis, p53 signaling, Wnt signaling). In contrast to KC and hepatocytes, TGF- β signaling pathway was significantly downregulated in HCV infected LSEC. The system biology approach helped to identify distinct gene expression profiles in HCV infected LSECs, KCs and hepatocytes. Macrophages demonstrated a broad increase in IL-1β and NFκB-responsive proinflammatory cytokines and chemokines, which correlated with increasing severity of liver disease. In contrast, analysis of genes commonly expressed in LSEC with HCV infected liver showed significant overlap of pathways associated with angiogenesis, adhesion, ECMorganization, and regulation of defense/immune responses. ----- CONCLUSION: This is the first comprehensive gene expression analysis of LSEC that provided insight into the broad portrait of genomic changes associated with HCV infection. These genes are critical components of host immune and inflammatory pathways and provide new evidence that LSEC downregulate inflammation during HCV infection.