Autoimmunity to membrane proteins in the central nervous system has been increasingly recognized as a cause of neuropsychiatric disease. A key recent development was the discovery of antibodies to NMDA receptors in some cases of encephalitis, characterized by cognitive changes, memory loss, seizures, and sometimes long-term morbidity or mortality. Treatment approaches and experimental studies have largely focused on the pathogenic role of these autoantibodies. Passive antibody transfer to mice has provided useful insights but does not produce the full spectrum of the human disease. Here we describe a unique de novo autoimmune mouse model of anti-NMDA receptor encephalitis. Active immunization of immune competent mice with conformationally-stabilized, native-like NMDA receptors induced a fulminant encephalitis with behavioral and pathologic characteristics similar to those observed in the human disorder. Our results provide evidence for neuroinflammation and immune cell infiltration as a component of the autoimmune response in mice. Use of transgenic mice indicated that mature T cells as well as antibody-producing cells were required for disease induction. Our results provide insights into disease pathogenesis as well as a platform for testing mechanisms of disease initiation and therapeutic approaches.