Objective: To investigate the diagnostic value of serum levels of aquaporin-4 (AQP4) and matrix metalloproteinase-9 (MMP-9) in predicting malignant cerebral infarction in patients with cerebral infarction. Methods: The clinical data about 66 patients with hemisphere massive cerebral infarction were collected. According to clinical symptoms and brain computed tomography (CT) findings, the patients were divided into malignant cerebral infarction group (MCI) and non-MCI group. The serum levels of AQP4 and MMP-9 were detected 1, 4, 7 days. The diagnostic value of AQP4 and MMP-9 in predicting occurrence of MCI was analysed by receiver operating characteristic (ROC) curve. Results: The serum levels of AQP4 and MMP-9 in MCI group were significantly higher than those in non-MCI group in the fourth day (P<0.05). In MCI group, AQP4 and MMP-9 in the fourth day were significant higher than other two time points (P<0.05). But in non-MCI group, AQP4 and MMP-9 in different time points have no differences (P>0.05). ROC curve analysis showed that the aera under curve for the serum levels of AQP4 was 0.654 (95% CI: 0.516-0.792). When the serum AQP4=23.49 μg/L, the sensitivity and specificity were 0.57, 0.74, respectively. Conclusions Serum AQP4 and MMP-9 levels were increased in patients with MCI. Combined detection of serum AQP4 and MMP-9 is helpful for early differential diagnosis of MCI.