Objective <p>This study aimed to examine the relationship between serum lipoprotein-associated phospholipase A2 (Lp-PLA2) levels and cognitive impairment (CI) in patients with chronic kidney disease (CKD).</p> Methods <p>A total of 125 patients with CKD treated in the Department of Nephrology, The Second Affiliated Hospital of Nantong University from July 2022 to May 2023 were selected and divided into observation group (44 patients with CI) and control group (81 patients with normal cognitive function). Multivariate logistic regression analysis was performed to analyze the risk factors of CI, and Spearman rank correlation analysis was used to analyze the correlation between serum Lp-PLA2 and Montreal Cognitive Assessment Scale (MoCA) score. The truncation value of Lp-PLA2 in CKD patients with CI was analyzed by receiver operating characteristic curve (ROC).</p> Results <p>Serum Lp-PLA2 levels were significantly elevated in the observation group compared to the control group (<i>P</i> &lt; 0.05). The area under the ROC curve for Lp-PLA2 was 0.849, with a cutoff value of 232&#xa0;ng/mL for identifying CI in patients with CKD. Lp-PLA2 levels were independently associated with CI in patients with CKD (odds ratio [OR] = 0.988, 95% confidence interval [CI]: 0.982–0.993, <i>P</i> &lt; 0.001).</p> Conclusion <p>Elevated serum Lp-PLA2 levels serve as an independent risk factor for CI in patients with CKD.</p>