Habituation enables the organism to attend selectively to novel stimuli by diminishing no-longer necessary responses to repeated stimuli. Because the prefrontal cortex (PFC) has a core role in monitoring attention and behavioral control especially under novelty, neural habituation responses may be modified in drug addiction, a psychopathology that entails PFC abnormalities in both structure and function. Sixteen cocaine abusers and 12 gender-, race-, education-, and intelligence-matched healthy control subjects performed an incentive sustained attention task twice, under novelty and after practice, during functional magnetic resonance imaging. For cocaine abusers practice effects were noted in the PFC (including anterior cingulate cortex/ventromedial rostral PFC, dorsolateral PFC, and medial frontal gyrus) and cerebellum (signal attenuations/decreases: return to baseline); activations in these regions were associated with craving, frequency of use, and length of abstinence. In the control subjects practice effects were instead restricted to posterior brain regions (precuneus and cuneus) (signal amplifications/increases: deactivation away from baseline). Also, only in the cocaine abusers, increased speed of behavioral performance between novelty to practice was associated with a respective attenuation of activation in the thalamus. Overall, we report for the first time a differential pattern of neural responses to repeated presentation of an incentive sustained attention task in cocaine addiction. Our results suggest a disruption in drug addiction of neural habituation to practice that possibly encompasses opponent anterior vs. posterior brain adaptation to the novelty of the experience: overly expeditious for the former but overly protracted for the latter. Overall, cocaine addicted individuals may be predisposed to an increased challenge when required to maintain alertness as a task progresses, not able to optimally utilize a prematurely habituating PFC to compensate with an increased attribution of salience to a desired reward.