Long-term cocaine and alcohol use is associated with neuropsychological impairments that implicate poor inhibitory mechanisms of behavioural control. This study tested acquisition and discrimination-reversal learning in a group of polydrug users (n 20) with a history of cocaine and heavy alcohol use and a group of age-matched controls (n 20). A cued go/nogo task measured subjects' ability to learn stimulus-response associations that involved the quick activation and sudden inhibition of responses. Compared with controls, drug users displayed similar acquisition, but impaired discrimination-reversal learning of both inhibitory and activational responses. The results suggest that some drug-related neuropsychological deficits might reflect specific impairments of the ability to inhibit interference from prior learning. The findings contribute to growing evidence that suggests cocaine and alcohol use could produce broad inhibitory impairments that increase the risk for learning deficits and poor impulse control.