A 46-year-old man inhaled combustible smoke of unknown chemical composition for 15-20 min in an automobile body shop. Within 1 month, he noted headache, sadness, anergia, anhedonia, agitation, poor sleep and impairment of concentration, attention and learning skills. Three years later, mental status examination showed major depression and cognitive disorder manifested by apprehension, continuous sadness, agitation, exhaustion, difficulty with word finding, bradyphrenia, short-term and long-term memory impairment, and judgement impaired by impulsive and affect-laden reactions without reflection. Impairments were noted on neuropsychiatric tests, and positron emission tomography (PET) scan of the brain with (18)F-fluorodeoxyglucose showed globally decreased and heterogeneous metabolic activity in the entire brain. Treatment included sertraline, methylphenidate, valproic acid and topiramate. At 14 years after smoke inhalation injury, he had persistent cognitive impairment. Repeat brain PET scan showed areas of improvement and deterioration. This case shows long-term brain and psychiatric dysfunction resulting after toxic smoke inhalation, with some areas of the brain having progressive deterioration between years 3 and 14 after smoke inhalation.