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This prospective study investigated the relationship between the lipoprotein-associated phospholipase A2 (Lp-PLA2) level and cognitive impairment (CI) in type II diabetes mellitus (TIIDM) patients with white matter hyperintensity (WMH). A total of 87 TIIDM patients diagnosed with WMH were included in this study. They were grouped into CI group and noncognitive impairment (NCI) group based on the MoCA scales. The serum Lp⁃PLA2 levels and MoCA scores of the patients with WMH were compared with those of control (Ctl). Logistic regression was used to analyze the risk factors affecting CI and diagnostic value of serum Lp⁃PLA2 for CI. The WMH group had significantly higher serum level of Lp⁃PLA2 and significantly lower MoCA score than Ctl group. There were significant differences in serum levels of homocysteine, high-density lipoprotein cholesterol (HDL-C) and Lp⁃PLA2 (P < 0.05) between the groups. Logistic regression showed that HDL-C, homocysteine and Lp⁃PLA2 were the risk factors for CI in the patients (P < 0.05); receiver operating characteristic curve analysis showed that HDL-C and Lp⁃PLA2 had significant diagnostic value for CI in WMH patients. Therefore, Lp⁃PLA2 can be assessed in the elderly as a screening to identify putative CI patents for preventive treatment and management.