Haptoglobin (Hp) scavenges cell-free hemoglobin and correlates with theprognosis of human sepsis, a life-threatening systemic inflammatory condi-tion. Despite extensive research on Hp glycosylation as a glyco-biomarker forcancers, understanding glycosylated modifications of Hp in sepsis patients(SPs) remains limited. Our study reveals elevated levels of terminal fucosyla-tion at Asn207 and Asn211 of Hp in SP plasma, along with heightened inflam-matory responses, compared to healthy controls (trial registrationNCT05911711). Fucosylated (Fu)-Hp purified from SPs upregulates inflamma-tory cytokines and chemokines, along with NLRP3 inflammasome activation.Single-cell RNA sequencing identifies a distinct macrophage-like cell popula-tion with increased expressions of inflammatory mediators and FUT4 inresponse to Fu-Hp. Additionally, Mincle, a C-type lectin receptor, interacts withFu-Hp to amplify the inflammatory responses and signaling. Moreover, the Hpfucosylation (AAL) level significantly correlates with the levels of inflammatorycytokines in sepsis patients, suggesting that Fu-Hp is clinically relevant. Finally,Fu-Hp treatment significantly enhances the levels of inflammatory cytokines inthe plasma and various tissues of mice. Together, our findings reveal a role ofFu-Hp, derived from sepsis patients, in driving inflammation, and suggest thattargeting Fu-Hp could serve as a promising intervention for combating sepsis.Trial registration NCT05911711