BACKGROUND: Substance misuse is a major public health issue and research has established attenuated reward responses to drug cues in those who misuse substances. Yet, little is known about whether the expectation of natural reinforcers engages distinct brain regions in substance misuse. METHODS: Using functional magnetic resonance imaging (fMRI), we delivered juice at expected and unexpected times to examine reward processing dysfunctions. We focused on the responses within the left dorsal striatum (DS) in individuals with high-risk substance use (HRU, n = 65), low-risk substance use (psychiatric controls, PC, n = 65), and healthy controls (HC, n = 65). Additionally, we investigated whether the dysfunction in reward processing within the left DS is correlated with other common psychiatric symptoms. Finally, we conducted a comprehensive analysis of the whole brain to investigate other non-hypothesized brain regions. RESULTS: Compared to HC, HRU displayed lower responses to juice delivery (i.e., reward) in the left DS (p <.05). The whole-brain analysis demonstrated that compared to HC, HRU displayed significantly lower responses to reward stimuli in various brain regions, including the bilateral caudate, temporal gyrus, left frontal gyrus, middle frontal gyrus, and right thalamus. LIMITATIONS: Participants were individuals with polysubstance use; therefore, we were not able to examine the effects of individual substances. CONCLUSIONS: Our findings suggest that HRU displays lower responses to reward stimuli within the left DS and other non-hypothesized brain regions. Our findings may help further elucidate reward processing dysfunctions related to substance misuse.