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Patient-tailored treatment, also known as precision-medicine, has been emphasized as a prioritized area in traumatic brain injury research. In fact, pre-injury patient genetic factors alone account for almost 26% of outcome prediction variance following traumatic brain injury. Among implicated genetic variants single-nucleotide polymorphism in apolipoprotein E has been linked to worse prognosis following traumatic brain injury, but the underlying mechanism is still unknown. We hypothesized that apolipoprotein E genotype would affect the levels of pathophysiology-driving structural, or inflammatory, proteins in cerebral microdialysate following severe traumatic brain injury. We conducted a prospective observational study of patients with severe traumatic brain injury treated with invasive neuromonitoring including cerebral microdialysis at Uppsala University Hospital. All patients were characterized regarding apolipoprotein E genotype. Utilizing fluid- and plate-based antibody arrays, we quantified 101 proteins (of which 89 were eligible for analysis) in cerebral microdialysate at 1 day and 3 days following trauma. Statistical analysis included clustering techniques, as well as uni- and multi-variate linear mixed modelling. In total, 26 patients were included, and all relevant genotypes of apolipoprotein E were represented in the data. Among all proteins tested, 41 proteins showed a time-dependent expression level. There was a weak clustering tendency in the data, and not primarily to genotype, either depicted through t-distributed stochastic neighbour embedding or hierarchical clustering. Using linear mixed models, two proteins [the inflammatory protein CD300 molecule like family member f (CLM-1) and the neurotrophic protein glial-derived neurotrophic factor family receptor α1] were found to have protein levels concomitantly dependent upon time and genotype, albeit this effect was not seen following multiple testing corrections. Apart from amyloid-β-40 (Aβ) and Microtubule-associated protein tau, neither Aβ peptide levels nor the Aβ42/40 ratio were seen related to time from trauma or apolipoprotein E genotype. This is the first study in clinical severe traumatic brain injury examining the influence of apolipoprotein E genotype on microdialysate protein expression. Protein levels in cerebral microdialysate following trauma are seen to be strongly dependent on time from trauma, corroborating previous work on protein expression longitudinally following traumatic brain injury. We also identified protein expression level alterations dependent on apolipoprotein E genotype, which might indicate that apolipoprotein E affects ongoing pathophysiology in the injured brain at the proteomic level.