ABSTRACTBackground and Objective: Neuronal pentraxin 2 (NPTX2) is associated with cognitive impairment in some neurodegenerative diseases. However, few studies focused on the association between NPTX2 and poststroke cognitive impairment (PSCI). Hence, this study aimed to investigate the association between serum NPTX2 levels and PSCI.Methods: A total of 134 participants with acute ischemic stroke (AIS) and 42 normal controls were enrolled in this study. Admission baseline information was collected, and serum NPTX2 levels were determined within 24 h using enzyme‐linked immunosorbent assay (ELISA) at hospital admission. All subjects were evaluated for cognitive function using the MoCA (Montreal Cognitive Assessment) scale at 3 months after stroke onset, and patients with AIS were divided into PSCI and PSNCI (poststroke no cognitive impairment) groups, with a total MoCA score < 26 defined as PSCI. This study analyzed the relationship between serum NPTX2 and MoCA score and the risk factors of PSCI. The receiver operating characteristic (ROC) curve was to evaluate the diagnostic value of serum NPTX2 levels on PSCI.Results: Among the 134 AIS participants, 53 (38.8%) patients suffered from PSCI at 3 months after stroke onset. The serum levels of NPTX2 in the PSCI group, PSNCI group, and normal controls group were significantly different (p < 0.05). The serum NPTX2 levels in the PSCI and PSNCI groups were higher than normal control group, and the serum NPTX2 levels in the PSCI group were lower than PSNCI group (p < 0.05). Serum NPTX2 levels were positively correlated with the total score of MoCA (r = 0.329, p < 0.01), and also positively correlated with some subcognitive domains of MoCA (visuospatial and executive functions, naming, delayed memory, and attention). ROC curve indicated that serum NPTX2 predicted cognitive impairment in AIS patients. Multivariate Logistic regression analysis indicated serum NPTX2 was an independent protective factor for PSCI (odds ratio [OR] = 0.075, 95% CI 0.010–0.812, p < 0.01).Conclusions: Lower serum NPTX2 levels were associated with PSCI within 3 months in patients with first‐episode AIS. Lower levels of serum NPTX2 may be associated with impairment in visuospatial and executive functions, naming, delayed memory, and attention, while a further larger‐scale study is needed to verify our findings.