Disorientation is a frequent consequence of acute brain injury or diffuse disorders, such as confusional states or dementia. Its anatomical correlates are debated. Impaired memory as its commonly assumed mechanism predicts that disorientation is associated with medial temporal damage. The alternative is that disorientation reflects defective orbitofrontal reality filtering (ORFi) – a specific failure to identify whether thoughts or memories refer to present reality or not. The latter is a function of the posterior orbitofrontal cortex and connected structures. This study examined the mechanisms and anatomical basis of disorientation in an unselected group of patients with first-ever subacute brain injury. Participants hospitalized for neurorehabilitation were asked to participate in this observational cohort study if they had first-ever organic hemispheric brain dysfunction as evident in a localizable brain lesion or verbal amnesia (often without localizable brain damage). Orientation to time, place, situation and person was tested with a 20-items questionnaire. To identify the mechanisms of disorientation, we determined its correlations with executive tasks, verbal episodic memory, and ORFi in all patients. ORFi was examined with a continuous recognition task, which measures learning and item recognition in the first run, and ORFi as reflected in the increase of false positive responses in the second run (temporal context confusion). Lesions of patients having localizable brain damage were manually delineated and normalized before entering multivariate lesion-symptom-mapping (LSM) to determine anatomical predictors of orientation. Eighty-four patients (61.1 ± 14.4 years, 29 women) were included. Among measures of memory and executive functioning, a step-wise regression retained temporal context confusion (R = −0.71, p < 0.0001), item recognition (R = 0.67, p < 0.0001) and delayed free recall (R = 0.63, p < 0.0001) as significant predictors of orientation. LSM was possible in 67 participants; it revealed an association of disorientation with damage of the right OFC and the bilateral head of the caudate nucleus. Disorientation in non-confused, non-demented patients with first-ever brain damage is associated with impaired orbitofrontal reality filtering and memory dysfunction, but not with executive dysfunction. Its main anatomical determinant is damage to the orbitofrontal cortex and its subcortical relay, the head of the caudate. • Disorientation is frequent after acute brain lesions, confusional state and dementia. • The mechanisms and anatomical basis of disorientation are poorly understood. • We explored the mechanisms and anatomical basis in a cohort of unselected patients with first-ever brain damage. • Impaired reality filtering and deficient learning are the strongest predictors of disorientation. • Multivariate lesion-symptom mapping identified the orbitofrontal cortex and head of caudate. [ABSTRACT FROM AUTHOR]