Background: Infants and preschoolers with ASD show impairment in their responses to other people's distress relative to children with other developmental delays and typically developing children. This deficit is expected to disrupt social interactions, social learning, and the formation of close relationships. Response to distress has not been evaluated previously in infants with ASD earlier than 18 months of age. Methods: Participants were 103 infant siblings of children with autism and 55 low-risk controls. All children were screened for ASD at 36 months and 14 were diagnosed with ASD. Infants' responsiveness to distress was evaluated at 12, 18, 24, and 36 months. An examiner pretended to hit her finger with a toy mallet and infants' responses were video-recorded. Attention to the examiner and congruent changes in affect were coded on four-point Likert scales. Results: Cross-sectional and longitudinal analyses confirm that the ASD group paid less attention and demonstrated less change in affect in response to the examiner's distress relative to the high-risk and low-risk participants who were not subsequently diagnosed with ASD. Group differences remained when verbal skills and general social responsiveness were included in the analytic models. Conclusions: Diagnostic groups differ on distress response from 12 to 36 months of age. Distress-response measures are predictive of later ASD diagnosis above and beyond verbal impairments. Distress response is a worthwhile target for early intervention programs.