Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory factor in the pathogenesis of atherosclerotic plaque and is associated with an increased risk of ischemic stroke. Whether Lp-PLA2 is associated with stenosis subtypes in acute ischemic stroke (AIS) has not been investigated.A total of 126 eligible AIS patients were divided into four groups: (1) no cerebral artery stenosis (NCS); (2) intracranial artery stenosis (ICAS); (3) extracranial artery stenosis (ECAS); and (4) combined intracranial and extracranial artery stenosis (IECS). Associations between serum Lp-PLA2 levels and the stenosis subtypes were assessed.The ICAS group had a lower frequency of dyslipidemia as compared to the NCS group and the IECS group (35.3% vs. 70% vs. 71.8%, respectively, p = 0.001) and was more likely to be symptomatic than the ECAS group (76.5% vs. 43.8%, respectively, p = 0.014). Lp-PLA2 levels in the ICAS group were 112.2 ± 66.8 μg/L which are, higher than those in the NCS, ECAS, and IECS groups (81.7 ± 38.5, 106.1 ± 57.8, 89.3 ± 52.2 μg/L, respectively, p = 0.025). In the third and fourth quartiles of Lp-PLA2 levels, stenosis had occurred more frequently in the ICAS group than in the other three groups (third Q: 50.0% vs. 3.1% vs. 28.1% vs. 18.8%, p = 0.002; fourth Q: 48.4% vs. 16.1% vs. 25.8% vs. 9.7%, p = 0.014). Lp-PLA2 levels were higher in patients with more or severe stenosis in the ICAS group.Elevated Lp-PLA2 levels were differentially associated with increased risk in AIS patients with ICAS compared to those with ECAS or no stenosis. Lp-PLA2 may be a promising biomarker and potential therapeutic target for ICAS.Copyright © 2022 Wang, Liu, Song, Cao, Ji and Cao.