This functional magnetic resonance imaging study compared the neural activation patterns of 18 high-functioning individuals with autism and 18 IQ-matched neurotypical control participants as they learned to perform a social judgment task. Participants learned to identify liars among pairs of computer-animated avatars uttering the same sentence but with different facial and vocal expressions, namely those that have previously been associated with lying versus truth-telling. Despite showing a behavioral learning effect similar to the control group, the autism group did not show the same pattern of decreased activation in cortical association areas as they learned the task. Furthermore, the autism group showed a significantly smaller increase in interregion synchronization of activation (functional connectivity) with learning than did the control group. Finally, the autism group had decreased structural connectivity as measured by corpus callosum size, and this measure was reliably related to functional connectivity measures. The findings suggest that cortical underconnectivity in autism may constrain the ability of the brain to rapidly adapt during learning.