Propofol, an anesthetic agent acting as an analogue of vitamin E, has been advocated to be an ideal neuroprotective agent both in animal models and in clinical practice, due to its positive effects on oxidative stress. Nevertheless, no studies have compared this agent to another sedative agent used for sedation after traumatic brain injury (TBI). The objective was to compare the effects of propofol to midazolam on cerebral biomarkers at the acute phase of severe TBI patients. Thirty patients aged 35±18 years were prospectively randomized to receive propofol or midazolam and 29 were analyzed (n=15 for propofol, and n=14 for midazolam). A cerebral microdialysis catheter was used to measure the lactate:pyruvate (L:P) ratio, glutamate, glycerol, and glucose for 72 h. No difference between groups was observed for the L:P ratio (time effect p=0.201, treatment effect p=0.401, time×treatment interaction p=0.101). Similarly, no difference was observed for glutamate (time effect p=0.930, treatment effect p=0.651, time×treatment interaction p=0.353), glycerol (time effect p=0.223, treatment effect p=0.922, time×treatment interaction p=0.308), or glucose (time effect p=0.116, treatment effect p=0.088, time×treatment interaction p=0.235). These results do not support a difference between propofol and midazolam for sedation for the cerebral metabolic profile in severe TBI.