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Arginine deficiency is involved in thrombocytopenia and immunosuppression in severe fever with thrombocytopenia syndrome. Arginine arbitrates thrombocytopenia: SFTS virus is a bunyavirus named for the disease it causes, severe fever with thrombocytopenia syndrome. It has only recently been discovered, and little is known about its pathogenesis or how to intervene. Li et al. conducted an observational study in a hospital setting to identify differences between fatal cases and those that went on to recover and discovered that decreased arginine was associated with thrombocytopenia and death. They then performed a randomized controlled clinical trial to supplement patients with arginine. Patients receiving arginine had decreased platelet activation and faster viral clearance. This study may pave the way for a better understanding and treatment for SFTS virus. Severe fever with thrombocytopenia syndrome (SFTS) caused by a recently identified bunyavirus, SFTSV, is an emerging infectious disease with extensive geographical distribution and high mortality. Progressive viral replication and severe thrombocytopenia are key features of SFTSV infection and fatal outcome, whereas the underlying mechanisms are unknown. We revealed arginine deficiency in SFTS cases by performing metabolomics analysis on two independent patient cohorts, suggesting that arginine metabolism by nitric oxide synthase and arginase is a key pathway in SFTSV infection and consequential death. Arginine deficiency was associated with decreased intraplatelet nitric oxide (Plt-NO) concentration, platelet activation, and thrombocytopenia. An expansion of arginase-expressing granulocytic myeloid-derived suppressor cells was observed, which was related to T cell CD3-ζ chain down-regulation and virus clearance disturbance, implicating a role of arginase activity and arginine depletion in the impaired anti-SFTSV T cell function. Moreover, a comprehensive measurement of arginine bioavailability, global arginine bioavailability ratio, was shown to be a good prognostic marker for fatal prediction in early infection. A randomized controlled trial demonstrated that arginine administration was correlated with enhanced Plt-NO concentration, suppressed platelet activation, and elevated CD3-ζ chain expression and eventually associated with an accelerated virus clearance and thrombocytopenia recovery. Together, our findings revealed the arginine catabolism pathway–associated regulation of platelet homeostasis and T cell dysregulation after SFTSV infection, which not only provided a functional mechanism underlying SFTS pathogenesis but also offered an alternative therapy choice for SFTS. [ABSTRACT FROM AUTHOR]