Objective: To investigate the changes in levels of Lp PLA2 and miR-221 before and after intravenous thrombolysis treatment for acute cerebral infarction, as well as the prognostic factors. Methods: A retrospective analysis was conducted on 180 patients with acute cerebral infarction admitted to our hospital from 2021.8-2024.8. According to the pathological diagnosis of stenosis, the patients were divided into mild group (n=40), moderate group (n=80), and severe group (n=60). The expression levels of serum Lp-PLA2 and miR-221 were compared among the three groups of patients. All patients received intravenous thrombolysis treatment, and the changes in Lp-PLA2 and miR-221 levels before and after thrombolysis treatment were compared in 180 patients. All patients were followed up for 6 months after thrombolytic therapy, and their prognosis was evaluated using the Improved Rankin Rating Scale (mRS). According to the different prognosis levels, 180 patients were divided into two subgroups. 40 patients with mRS scores ≥ 3 were classified as poor prognosis group, and 140 patients with mRS scores<3 were classified as good prognosis group. The logistic regression model was used to analyze the prognostic factors of intravenous thrombolysis treatment for acute cerebral infarction. Results: The relative expression levels of Lp PLA2 (327.52±47.15) ng/mL and miR-221 (3.24±0.24) in the severe group of acute cerebral infarction were higher than those in the mild and moderate groups (P<0.05); After thrombolysis treatment, the relative expression levels of Lp PLA2 (187.76±43.29) ng/mL and miR-221 (1.32±0.24) in patients with acute cerebral infarction were lower than before treatment (P<0.05); There was no significant difference in gender, BMI, time from onset to thrombolysis, comorbidities with underlying diseases, and use of antiplatelet aggregation drugs before thrombolysis between the poor prognosis group and the poor prognosis group (P>0.05). The age of the poor prognosis group, NIHSS score before thrombolysis, relative expression levels of Lp-PLA2 and miR-221 were all higher than those in the control group, and there were statistically significant differences in ischemic stroke history, infarct site, comorbidities with white matter lesions, cerebral atrophy, and complications of cerebral edema (P<0.05); The NIHSS score before thrombolysis, history of ischemic stroke, concomitant white matter lesions, relative expression levels of Lp-PLA2 and miR-221 were independent prognostic factors for intravenous thrombolysis treatment of acute cerebral infarction (P<0.05). Conclusion: The levels of Lp PLA2 and miR-221 can increase with the aggravation of acute cerebral infarction patients, and their expression levels can decrease after treatment. The NIHSS score before thrombolysis, relative expression levels of Lp PLA2 and miR-221 are also increased. History of ischemic stroke and concomitant white matter lesions can affect the prognosis of intravenous thrombolysis for acute cerebral infarction.