Cue-reactivity reflects enhanced motivational processing underlying continued substance use and relapse in substance use disorders. Substance use disorders are associated with greater cue-reactivity in orbitofrontal cortex, anterior cingulate cortex, striatum, ventral tegmental area and amygdala. Here we examine whether this also holds for frequent cannabis users. Using functional magnetic resonance imaging (fMRI), neural responses to neutral and cannabis-related cues were compared between frequent cannabis users (n = 31), sporadic cannabis users (n = 20) and cannabis-naive controls (n = 21). In addition, fMRI findings were correlated with the level of cannabis use, problem severity and craving. In frequent users compared with sporadic users and controls, cannabis images engendered higher activation than control images in the ventral tegmental area. Activation of the orbitofrontal cortex, anterior cingulate cortex and striatum was only higher in a subgroup of frequent users with high compared with low-problem severity. Activity in the right putamen and right dorsolateral prefrontal cortex correlated negatively with subjective craving in frequent users. Activity was not correlated with level of cannabis use. These findings indicate that cannabis cues activate areas associated with addiction pathology in frequent cannabis users compared with sporadic users and controls. However, among frequent users, cue-reactivity seems to be primarily associated with problem severity, not with amount of cannabis use. These findings imply neural cue-reactivity as a tool in assessing problem severity of cannabis use.