Abstract: Objective To investigate the expression and clinical significance of serum osteopontin (OSM) and soluble tumor necrosis factor receptor 1 (sTNF-R1) levels in patients with lacunar infarction (LI). Methods A total of 218 patients with LI (LI group) who were admitted to Nanjing Jiangbei Hospital from January and 109 healthy volunteers (control group) who underwent physical examinations in the same hospital from January 2022 to August 2024 were prospectively selected in a 2:1 ratio. According to their condition based on the National Institutes of Health Stroke Scale (NIHSS), LI patients were further classified into a severe LI group (n=99) and a mild LI group (n=119) and then re-divided into a vascular cognitive impairment (VCI) group and a non-VCI group based on the occurance of VCI six months after the stroke. Their levels of serum OSM and sTNF-R1 were measured by enzyme-linked immunosorbent assay (ELISA), and the correlation between these levels and NIHSS scores were assessed by Spearman's correlation analysis. Multivariate logistic regression and receiver operating characteristic (ROC) curve analysis were performed to explore the relationship and predictive efficicency of serum OSM and sTNF-R1 levels in predicting the occurrence of VCI in LI patients. Results Compared with the control group, elevated levels of serum OSM and sTNF-R1 were observed in the LI group (P<0.05). The severe LI group showed higher serum OSM and sTNF-R1 levels than the mild LI group (P<0.05). Serum levels of OSM and sTNF-R1 in LI patients were positively correlated with NIHSS scores (r_s/P=0.687/<0.001, 0.715/<0.001). Compared with the non-VCI group, the VCI group showed increased serum OSM and sTNF-R1 levels (P<0.05). Age, moderate to severe white matter lesions, high NIHSS scores, large infarct volume, high total load score of cerebral small vessel disease, and high serum OSM and sTNF-R1 levels were identified as independent risk factors for developing VCI in LI patients (P<0.05). The area under the curve (AUC) for serum OSM, sTNF-R1, and their combination in predicting VCI in LI patients was 0.805, 0.824, and 0.909, respectively. The combined prediction model was more effective than either OSM or sTNF-R1 alone (P<0.05). Conclusions Elevated serum OSM and sTNF-R1 levels in LI patients are associated with disease severity and the development of VCI. The combined measurement of OSM and sTNF-R1 provides high predictive efficiency for VCI in LI patients.