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Reinstatement is the recovery of previously extinguished responding during response-independent delivery of previously reinforcing stimuli. In this translational study, we examined reinstatement of severe destructive behavior exhibited by individuals with autism. First, destructive behavior was reinforced on a fixed-ratio 1 schedule of reinforcement, and high rates of responding were observed. Next, extinction was implemented and destructive behavior ceased. In the third component, a fixed-time, 2-min schedule of reinforcement was implemented and destructive behavior was reinstated. The 3-component sequence of conditions was implemented two additional times with both participants, and destructive behavior recurred during each test for reinstatement. These results suggest that reinstatement (a) occurs across populations and topographies of behavior, including clinically relevant responses such as destructive behavior, and (b) is a mechanism that may represent a challenge to treatment and play a role in clinical relapse of destructive behavior.