This study investigates anti-NMDA-receptor encephalitis, a severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor. The authors analyzed the clinical and immunological features of 100 patients with this disorder and examined the effects of these antibodies on neuronal cultures. The median age of patients was 23 years, and 91 were women. All patients presented with psychiatric symptoms or memory problems, and many also had seizures, unresponsiveness, dyskinesias, autonomic instability, and hypoventilation. Over half of the patients had tumors, most commonly ovarian teratoma. Early tumor treatment (usually with immunotherapy) was associated with better outcomes and fewer neurological relapses. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients' antibodies decreased the number of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. The findings suggest that the pathogenesis of anti-NMDA-receptor encephalitis is mediated by antibodies, and that the disorder is often treatable and can be diagnosed serologically.This study investigates anti-NMDA-receptor encephalitis, a severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor. The authors analyzed the clinical and immunological features of 100 patients with this disorder and examined the effects of these antibodies on neuronal cultures. The median age of patients was 23 years, and 91 were women. All patients presented with psychiatric symptoms or memory problems, and many also had seizures, unresponsiveness, dyskinesias, autonomic instability, and hypoventilation. Over half of the patients had tumors, most commonly ovarian teratoma. Early tumor treatment (usually with immunotherapy) was associated with better outcomes and fewer neurological relapses. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients' antibodies decreased the number of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. The findings suggest that the pathogenesis of anti-NMDA-receptor encephalitis is mediated by antibodies, and that the disorder is often treatable and can be diagnosed serologically.