Difficulty with social interactions is a hallmark characteristic of autism spectrum disorders. While many studies have investigated the neural mechanisms underlying atypical social cognition, the methods used have rarely involved social interaction, relying instead on offline reasoning about a character. In the current study, we examined whether and which brain systems are sensitive to online social interactions in individuals with autism. We compared functional MRI data collected from 15 neurotypical (NT) and 15 autism spectrum disorder (ASD) participants during live real-time interactions (Live) and during a video replay of the same interaction (Recorded-Same) and a novel interaction (Recorded-Novel). Whole brain analyses demonstrated a significantly greater response to Live than Recorded conditions, in NT vs ASD, within left posterior superior temporal sulcus (pSTS) and regions of the cerebellum bilaterally. Region of interest analyses revealed that right posterior temporal regions were differentially recruited during online social interactions in the ASD and NT groups. Also, regions commonly associated with personal salience (i.e., dorsal anterior cingulate and bilateral insula) were sensitive to online social interactions in NT, but to novelty in the ASD group. These data suggest reduced and atypical neural sensitivity to online social interactions in individuals with autism.