Difficulty engaging in reciprocal social interactions is a core characteristic of autism spectrum disorder. The mechanisms supporting effective dynamic real-time social exchanges are not yet well understood. This proof-of-concept hyperscanning electroencephalography study examined neural synchrony as the mechanism supporting interpersonal social interaction in 34 adolescents with autism spectrum disorder, age 10–16 years, paired with neurotypical confederates of similar age. The degree of brain-to-brain neural synchrony was quantified at temporo-parietal scalp locations as the circular correlation of oscillatory amplitudes in theta, alpha, (...) and beta frequency bands while the participants engaged in a friendly conversation. In line with the hypotheses, interpersonal neural synchrony was significantly greater during the social interaction compared to the baseline. Lower levels of synchrony were associated with increased behavioral symptoms of social difficulties. With regard to sex differences, we found evidence for stronger interpersonal neural synchrony during conversation than baseline in females with autism, but not in male participants, for whom such condition differences did not reach statistical significance. This study established the feasibility of hyperscanning during real-time social interactions as an informative approach to examine social competence in autism, demonstrated that neural coordination of activity between the interacting brains may contribute to social behavior, and offered new insights into sex-related variability in social functioning in individuals with autism spectrum disorders. (shrink)