Background <p>This study aimed to characterize the clinical impact of Epstein-Barr virus (EBV) super-infection in patients with Hemorrhagic Fever with Renal Syndrome (HFRS).</p> Methods <p>A cohort of 126 confirmed HFRS patients were enrolled and stratified into EBV (<i>n</i> = 62) and Non-EBV (<i>n</i> = 64) groups based on PCR detection of the EBV IR1 gene. Clinical manifestations and serial laboratory parameters assessing multi-organ function were compared.</p> Result <p>HFRS patients super-infected with EBV exhibited a significantly higher frequency of neurological and gastrointestinal symptoms, including dizziness (50.0% vs. 26.6%), anorexia (95.2% vs. 82.8%), and diarrhea (50.0% vs. 15.6%). Laboratory findings revealed more severe multi-organ dysfunction in the EBV group, evidenced by significantly elevated markers of hepatic injury (γ-GGT, LDH), renal impairment (BUN, β2-MG, uric acid; decreased eGFR), cardiac stress (BNP), and thyroid suppression (T4, FT3). Additionally, the EBV group demonstrated heightened hematologic stress, with lower platelet counts and higher red cell distribution width. Immunological profiling showed a paradoxical state of intense cellular immune activation (elevated WBC, lymphocytes, neutrophils) coupled with suppressed systemic inflammatory markers (lower CRP and ESR).</p> Conclusions <p>EBV super-infection is associated with increased HFRS severity, exacerbating multi-organ dysfunction and inducing a distinct dysregulated immune response.</p> Clinical trial <p>Not applicable.</p>