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Human cell receptors are the first barriers to viral entry, proliferation, and host immune response. This study explored the association between single nucleotide polymorphisms (SNPs) in genes encoding receptors or related molecules that mediate SFTSV cell entry, such as dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), DC-SIGN-related protein (DC-SIGNR), and non-muscle myosin heavy chain IIA (NMMHC-IIA), and SFTSV infection susceptibility in the Chinese Han population, as well as the underlying potential biological mechanisms. From September 2020 to December 2022, 454 subjects from the First Affiliated Hospital with Nanjing Medical University were enrolled and divided into SFTSV-infected and uninfected groups based on SFTSV RNA and antibody test results. TaqMan SNP genotyping was performed on\n                      <jats:italic toggle=\"yes\">DC-SIGN<\/jats:italic>\n                      (rs7248637, rs4804800, and rs11465421),\n                      <jats:italic toggle=\"yes\">DC-SIGNR<\/jats:italic>\n                      (rs2277998), and\n                      <jats:italic toggle=\"yes\">NMMHC-IIA<\/jats:italic>\n                      (rs2269529 and rs2269530). Logistic regression was used to assess the association between the candidate SNPs and SFTSV infection susceptibility, and the online bioinformatics tools were employed to explore potential biological functions of positive SNPs. Logistic regression analysis showed that individuals carrying the\n                      <jats:italic toggle=\"yes\">DC-SIGNR<\/jats:italic>\n                      rs2277998 AA genotype were more susceptible to SFTSV infection, and\n                      <jats:italic toggle=\"yes\">in silico<\/jats:italic>\n                      bioinformatics analysis generated the hypothesis that this locus might be involved in influencing gene transcription and expression, which warrants further functional validation.\n                      <jats:italic toggle=\"yes\">DC-SIGNR<\/jats:italic>\n                      rs2277998 is significantly associated with SFTSV infection susceptibility in the Chinese Han population. The exact regulatory mechanisms require further experimental validation.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by severe fever with thrombocytopenia syndrome virus (SFTSV). Host genetic variation may modulate both disease susceptibility and severity by altering key functional proteins. Our study was the first to explore the association between single nucleotide polymorphisms (SNPs) in host genes encoding receptors or related molecules that mediate SFTSV cell entry, such as dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), DC-SIGN-related protein (DC-SIGNR), and non-muscle myosin heavy chain IIA (NMMHC-IIA), and SFTSV infection susceptibility in the Chinese Han population. The results showed that the homozygous mutation of\n                        <jats:italic toggle=\"yes\">DC-SIGNR<\/jats:italic>\n                        rs2277998 AA genotype was associated with a significantly higher risk of SFTSV infection in the Chinese Han population, with\n                        <jats:italic toggle=\"yes\">in silico<\/jats:italic>\n                        predictions pointing to a potential, yet unverified, role in regulating the\n                        <jats:italic toggle=\"yes\">DC-SIGNR<\/jats:italic>\n                        gene transcription and expression, which may provide a new scientific basis for SFTSV prevention and treatment.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  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