Current guidelines in traumatic brain injury (TBI) recommend a cerebral perfusion pressure (CPP) within the fixed interval of 60-70 mm Hg. However, the autoregulatory, optimal CPP target (CPPopt) might yield better cerebral blood flow (CBF) regulation. In this study, we investigated fixed versus autoregulatory CPP targets in relation to cerebral energy metabolism and clinical outcome after TBI. Ninety-eight non-craniectomized patients with severe TBI treated in the neurointensive care unit, Uppsala University Hospital, Sweden, 2008-2018, were included. Data from cerebral microdialysis (MD), intracranial pressure (ICP), pressure autoregulation, CPP and CPPopt55-15 (a variant of CPPopt based on filtered slow waves from 15-55 sec range) were analyzed the first 10 days. The good monitoring time (GMT %) below/within/above the fixed and autoregulatory CPP targets were calculated. CPPopt55-15 was >70 mm Hg 74% of the time the first 10 days. Higher GMT (%) ΔCPPopt55-15 ± 10 mm Hg correlated with lower lactate/pyruvate ratio (LPR) on day 1 and lower cerebral glycerol on days 6-10, and predicted favorable clinical outcome. Higher GMT (%) CPP within 60-70 mm Hg correlated with lower cerebral glucose on days 2-10 and higher LPR on days 6-10, but predicted favorable clinical outcome. Higher GMT (%) CPP >70 mm Hg had the opposite associations; that is, with higher cerebral glucose and lower LPR, but unfavorable clinical outcome. Autoregulatory CPP targets may be beneficial, because patients with CPP values close to the optimal CPP had both better cerebral energy metabolism and better clinical outcome, but this needs to be evaluated in randomized trials.