To determine if the inability to take advantage of the predictability of an aversive stimulus to diminish its psychological impact reflects a deficit in inhibitory control related to the development of substance dependence, we recorded skin conductance responses (SCRs), heart rate (HR), and anticipatory electrodermal nonspecific fluctuations (NSFs) from 175 16–18-year-old boys when a white noise blast was either unpredictable or temporally predictable. Compared with boys who had moderately reduced or augmented SCRs to predictable blasts (moderate and poor modulators, respectively), boys whose SCRs were greatly reduced (good modulators) had fewer symptoms of alcohol and nicotine dependence and more anticipatory NSFs. HR appeared to index an active coping response for good and moderate modulators. The autonomic response pattern evident for good modulators may index an inhibitory control mechanism protecting them from developing substance dependence.