OBJECTIVE To increase awareness of the incidence of delayed leukoencephalopathy in rehabilitation medicine. METHODS A 34-year-old male patient in an inpatient neuro-rehabilitation clinic who developed cognitive, psychological and physical deterioration 33 days after methadone intake. METHODS Clinical follow-up for 7 months, brain imaging with magnetic resonance imaging and computed tomography, electroencephalography, multidisciplinary team evaluation and rehabilitation, pharmacological treatment, and examination of medical records. RESULTS Clinical findings showed neuropsychological and motor deterioration. Brain images demonstrated that previous white matter infarctions had developed to cystic substance defects, and that abnormally high signals developed in the white matter of most cerebral lobes, with the exception of the grey matter and the cerebellum. Clinical improvement coincided with a modification in pharmacological treatment (increase in sertraline and introduction of baclofen). Brain images at 3 and 6 months after the methadone overdose showed reduced intensity of signal abnormalities and complete normalization of diffusion weighted images. Evaluation 7 months after injury estimated moderate brain injury with moderate disability and partial recovery of the patient's capacity for previous activities of daily living. CONCLUSIONS Delayed leukoencephalopathy should be suspected in patients who deteriorate after methadone overdose. Drugs such as sertraline and baclofen may be of use in treating delayed leukoencephalopathy.