Patients with traumatic brain injury (TBI) with large contusions make up a specific TBI subtype. Because of the risk of brain edema worsening, elevated cerebral perfusion pressure (CPP) may be particularly dangerous. The pressure reactivity index (PRx) and optimal cerebral perfusion pressure (CPPopt) are new promising perfusion targets based on cerebral autoregulation, but they reflect the global brain state and may be less valid in patients with predominant focal lesions. In this study, we aimed to investigate if patients with TBI with significant contusions exhibited a different association between PRx, CPP, and CPPopt in relation to functional outcome compared to those with small/no contusions. This observational study included 385 patients with moderate to severe TBI treated at a neurointensive care unit in Uppsala, Sweden. The patients were classified into two groups: (1) significant contusions (> 10mL) and (2) small/no contusions (but with extra-axial or diffuse injuries). The percentage of good monitoring time (%GMT) with intracranial pressure > 20mm Hg; PRx > 0.30; CPP < 60mm Hg, within 60-70mm Hg, or > 70mm Hg; and ΔCPPopt less than - 5mm Hg, ± 5mm Hg, or > 5mm Hg was calculated. Outcome (Glasgow Outcome Scale-Extended) was assessed after 6months. Among the 120 (31%) patients with significant contusions, a lower %GMT with CPP between 60 and 70mm Hg was independently associated with unfavorable outcome. The %GMTs with PRx and ΔCPPopt ± 5mm Hg were not independently associated with outcome. Among the 265 (69%) patients with small/no contusions, a higher %GMT of PRx > 0.30 and a lower %GMT of ΔCPPopt ± 5mm Hg were independently associated with unfavorable outcome. In patients with TBI with significant contusions, CPP within 60-70mm Hg may improve outcome. PRx and CPPopt, which reflect global cerebral pressure autoregulation, may be useful in patients with TBI without significant focal brain lesions but seem less valid for those with large contusions. However, this was an observational, hypothesis-generating study; our findings need to be validated in prospective studies before translating them into clinical practice.