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Few studies have examined whether familiarity of partner affects social responses in children with autism. This study investigated heart rate regulation (respiratory sinus arrhythmia [RSA]: The myelinated vagus nerve’s regulation of heart rate) and temporal–parietal electroencephalogram (EEG) activity while nineteen 8- to 12-year-old children with autism and 14 controls viewed videos of a familiar and an unfamiliar person reading a story. Children with autism had lower overall RSA levels and exhibited decreased RSA to the unfamiliar person, versus control children. Both groups decreased temporal–parietal EEG activity to the unfamiliar person. Higher RSA was related to higher social skill ratings and fewer problem behaviors. Thus, the social difficulties of children with autism may be characterized by specific mobilization to unfamiliar people.