Objective: To investigate the correlation of early intracranial pressure with CRP and D-dimer (D-D) in cerebrospinal fluid and peripheral blood in patients with severe traumatic brain injury after craniotomy, and to provide reference for the judgment of severe craniocerebral injury disease. Methods: Thirtyseven patients with severe craniocerebral injury treated by craniotomy in the Department of Neurosurgery from January 2015 to December 2017 was involved. Postoperative ICP of all patients were detected by intracranial pressure catheter. The cerebrospinal fluid and peripheral blood samples of patients were collected at each 12 h within 3 days after surgery, CRP and D-D were detected, and the corresponding ICP index at the time point was statistically analyzed. Results: A total of 222 copies of the data were obtained, in which 105 copies showed ICP >20 mmHg and 117 showed ≤20 mmHg. When ICP >20 mmHg, CRP and D-D in both serum and cerebrospinal fluid were higher than when ICP ≤20 mmHg (P<0.05). ICP was positive correlated with CRP in serum, D-D in serum, CRP in cerebrospinal fluid and D-D in cerebrospinal fluid (ρ=0.742, 0.884, 0.805, 0.886; all P<0.001). CRP in serum, D-D in serum, CRP in cerebrospinal fluid and D-D in cerebrospinal fluid were all reliable values for the diagnosis of ICP >20 mmHg. The area under ROC were 0.854, 0.943, 0.870, and 0.951, respectively. D-D in cerebrospinal fluid was an independent factor of ICP >20 mmHg (OR=4.115, P=0.001). Conclusion: The early postoperative ICP has positive correlation with serum and peripheral blood CRP and D-D in both cerebrospinal fluid and peripheral blood, and it is most closely related to CSF D-D. The combined detection of CRP and D-D in cerebrospinal fluid and peripheral blood can help to reflect the change of ICP in patients, so as to provide reference for postoperative treatment.