BACKGROUND. Encephalitis is a complex, debilitating, and sometimes fatal neurologic condition to which children are especially prone. Mycoplasma pneumoniae, a common respiratory pathogen, has been implicated as an etiology of encephalitis. Evidence for recent or acute M pneumoniae infection has been demonstrated in limited studies of both pediatric and adult patients with encephalitis. PATIENTS AND METHODS. Unexplained encephalitis cases are referred to the California Encephalitis Project for diagnostic testing. Serum, cerebrospinal fluid, and respiratory specimens are tested by polymerase chain reaction and serology methods for the presence of multiple pathogens, including M pneumoniae. M pneumonia–associated cases of encephalitis were compared with other bacterial agents, herpes simplex virus 1, and enterovirus. RESULTS. Of 1988 patients referred to the California Encephalitis Project, evidence of acute M pneumoniae infection was found in 111 patients, of which 84 (76%) were pediatric patients. Eighty percent of the 84 patients were positive for M pneumoniae by serology alone. Cerebrospinal fluid polymerase chain reaction for M pneumoniae was rarely positive (2%). Patients with M pneumoniae–associated pediatric encephalitis were a median of 11 years old, progressed rapidly (median: 2 days from onset to hospitalization), and were often in the ICU (55%). Symptoms included fever (70%), lethargy (68%), and altered consciousness (58%). Gastrointestinal (45%) and respiratory (44%) symptoms were less common. Compared with patients with other bacterial as well as viral agents, patients with M pneumoniae–associated encephalitis had fewer seizures and less-severe hospital courses. CONCLUSIONS. M pneumoniae is the most common agent implicated in the California Encephalitis Project. Patients with M pneumoniae–associated encephalitis are predominantly pediatric, and their presentations are clinically similar to enterovirus encephalitis, although they frequently require intensive care with prolonged hospitalizations. Given that M pneumoniae infection is found more than any other pathogen, increased emphasis should be placed on elucidating the role and mechanism of M pneumoniae in encephalitis.