Disturbed cerebral autoregulation (represented by a positive pressure reactivity index [PRx]), elevated intracranial pressure (ICP), and decreased cerebral perfusion pressure (CPP) are key treatment targets following severe traumatic brain injury (sTBI). This study investigated neuroinflammation as a potential mechanism underlying these intracranial disturbances. Plasma samples from 11 sTBI patients (from a prior Phase II drug trial) were analyzed for 174 proteins using an antibody-based suspension bead array, with intervention effects accounted for where possible. Dimensionality reduction techniques, including principal component analysis (PCA) and supervised methods, were applied to protein data, informed by physiological variables (ICP, CPP, and PRx). PCA revealed distinct protein clustering patterns related to ICP >20 mmHg and PRx > 0, with PC1 linked to patient ID, time from injury, and intervention, and PC2/PC3 significantly associated with PRx dose (p < 0.001). Markers relating to inflammation of the vascular system comprised 20% of the top 50 proteins influencing PC2, implicating complement inflammation in these processes. Notably, MASP-2 (p = 0.027) and complement factor I (p = 0.039) were significantly associated with PRx dose in a mixed-effects model. These findings suggest that vascular inflammation, particularly complement activation, may contribute to intracranial physiological disturbances in sTBI, highlighting the complement pathway as a potential target for further investigation.