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The aim of the study was to investigate sex-related differences in intracranial pressure (ICP) dynamics, cerebral pressure autoregulation (PRx55-15), cerebral energy metabolism, and clinical outcome after severe traumatic brain injury (TBI). One-hundred sixty-nine adult patients with TBI, treated at the Neurointensive Care (NIC) Unit at Uppsala University Hospital between 2008 and 2020 with ICP and cerebral microdialysis (MD) monitoring were included. Of the 169 patients with TBI, 131 (78%) were male and 38 (22%) female. Male patients were more often injured by motor vehicle accidents and less often by bicycle accidents (p < 0.05). There were otherwise no differences in age, neurological status at admission, and types of intracranial hemorrhages between the sexes. The percent of monitoring time with ICP above 20 mm Hg and cerebral perfusion pressure (CPP) below 60 mm Hg were similar for both sexes. Males exhibited more disturbed cerebral pressure autoregulation (PRx55-15 [mean +/- standard deviation (SD)]; 0.28 +/- 0.18 vs. 0.17 +/- 0.23, p < 0.05) on day 1, worse cerebral energy metabolism (MD-lactate-/pyruvate-ratio [median (interquartile range)]; 25 [19-31] vs. 20 [17-25], p < 0.01) and mitochondrial dysfunction (higher burden of MD-lactate-/pyruvate-ratio >25 and MD-pyruvate >120 mu M [median (interquartile range)]; 13 [0-58] % vs. 3 [0-17] %, p < 0.05) on days 2 to 5, increased excitotoxicity (MD-glutamate median [interquartile range]; 9 [4-32] mu M vs. 5 [3-10] mu M, p < 0.05) on days 2 to 5, and higher biomarker levels of cellular injury (MD-glycerol median [interquartile range]; 103 [66-193] mu M vs. 68 [49-106] mu M, p < 0.01) most pronounced on days 6 to 10. There was no difference in mortality or the degree of favorable outcome between the sexes.Altogether, females exhibited more favorable cerebral physiology post-TBI, particularly better mitochondrial function and reduced excitotoxicity, but this did not translate into better clinical outcome compared with males. Future studies are needed to further explore potential sex differences in secondary injury mechanisms in TBI.