Toxic irreversible encephalopathic syndromes developed in 2 patients treated with lithium carbonate and haloperidol. Symptoms consisted of lethargy, fever, tremulousness, confusion, and extrapyramidal and cerebellar dysfunction, accompanied by leucocytosis and elevated serum enzyme, blood urea nitrogen, creatinine and fasting blood glucose levels. One patient suffered widespread irreversible brain damage; the other was left with persistent dyskinesias. Although causal factors have not been identified, this report and others in the literature suggest that diffuse irreversible encephalopathy may occasionally develop in individuals with abnormal brain sensitivity to the lithium carbonate/haloperidol combination. Evidence for this is based on the fact that in our patients and others mentioned in the literature the dosage and blood levels of lithium were not high.