To analyze the correlation between serum caspase-cleaved cytokeratin 18 (CCCK-18) elevation and the occurrence and development of cerebral infarction secondary to traumatic epidural hematoma and concurrent cerebral herniation, and to clarify its early predictive ability and clinical decision-making value for secondary cerebral infarction. Methods: Preoperative serum CCCK-18 levels in 206 enrolled patients with cerebral herniation from isolated epidural hematoma were analyzed retrospectively for its potential correlation with the occupying volume of postoperative secondary cerebral infarction. Results: Post-operative secondary cerebral infarction was determined in 49 patients (23.78%). Among them, 32 cases (15.78%) had an occupying volume larger than 20 mL and were assigned to the massive cerebral infarction group; 17 cases (8.25%) had an occupying volume smaller than 20 mL and were assigned to the moderate cerebral infarction group, and the remaining 157 cases (76.21% ) were assigned to the non-cerebral infarction group. The concentration of CCCK-18 in the massive cerebral infarction group was significantly higher than that in the moderate cerebral infarction group and that in the non-cerebral infarction group (each P<0.001). The preoperative serum CCCK-18 level was linearly correlated with the occupying volume of secondary cerebral infarction (P<0.001). Receiver Operating Characteristic (ROC) showed that the area under the curve (AUC) of preoperative serum CCCK-18 was 0.814 (P<0.001), and the accuracy of assigning 241 U/L as the predictive threshold value was 83.50% . Multivariate logistic regression analysis showed that a >241 U/L preoperative serum CCCK-18 was an independent risk factor for postoperative massive cerebral infarction secondary to traumatic epidural hematoma and concurrent cerebral herniation. At the end of the 6-month follow-up, the GOS (Glasgow Outcome Scale) score of patients with serum CCCK-18 higher than 241 U/L was significantly lower than that of patients with levels lower than 241 U/L (P<0.001). Conclusion: Preoperative increased serum CCCK-18 is closely related to secondary massive cerebral infarction in patients with cerebral herniation from isolated epidural hematoma. It can serve as a useful biomarker for assisting decision-making of decompressive craniectomy surgery and predicting long-term neurological function.