Abstract: OBJECTIVE To investigate the value of serum syndecan-1 (SDC-1), fractalkine (FKN) and β-defensin 2 (HBD2) in the early diagnosis and prognostic evaluation of bloodstream infection. METHODS A total of 123 patients with bloodstream infection admitted to Qingdao Central Hospital, University of Health and Rehabilitation Sciences from Jun. 2022 to Jul. 2024 were selected as the infection group. According to the 4-week follow-up prognosis, they were divided into a survival group (94 cases) and a death group (29 cases). Additionally, 107 healthy individuals who underwent physical examinations during the same period were selected as the control group. Pearson correlation analysis was used to analyze the correlation among the three markers. The receiver operating characteristic (ROC) curve was employed to evaluate their diagnostic and prognostic value, and Cox regression analysis was used to identify prognostic risk factors. RESULTS The levels of serum SDC-1, FKN, HBD2, C-reactive protein (CRP), interleukin-6 (IL-6) and procalcitonin (PCT) in the infection group were significantly higher than those in the control group (P<0.05). The area under the curve (AUC) for the combined diagnosis of bloodstream infection with SDC-1, FKN and HBD2 was 0.895, which was superior to that of individual diagnoses (P<0.05). The AUC for the combined diagnosis with SDC-1, FKN and HBD2 (0.895) was higher than that for the combined diagnosis with CRP, IL-6 and PCT (0.801) (P<0.05). The levels of serum SDC-1, FKN and HBD2 in patients with bloodstream infection in the death group were higher than those in the survival group (P<0.05). There was a positive correlation among serum SDC-1, FKN and HBD2 (P<0.001). The AUC for the combined assessment of prognosis of patient with SDC-1, FKN and HBD2 was 0.921, which was superior to that of individual assessments (P<0.05). Elevated levels of SDC-1, FKN and HBD2 were risk factors for death in patients with bloodstream infection (P<0.05). CONCLUSIONS Serum SDC-1, FKN and HBD2 are highly expressed in patients with bloodstream infection. The combined use of these three markers exhibits good diagnostic efficacy and may serve as potential indicators for evaluating the prognosis of patients with bloodstream infection.