Objective: To compare SPECT at-rest blood perfusion across 17 brain regions, between Alcohol-Related Disorder, Cannabis-Related Disorder, and a no diagnosis group. Method: Participants from a clinical database (74.4% male, Mage = 35.77 years, SD = 14.42) were selected based on Alcohol-Related Disorder (n = 747), Cannabis-Related Disorder (n = 602), or no diagnosis (n = 83). Results: MANOVA conducted at alpha = 0.001 revealed significant group differences, Wilks’ Λ = 0.835; F(32, 2828) = 8.32, p < 0.001. There were significant differences in bilateral limbic, basal ganglia, cerebellum, frontal, occipital, motor/sensory, and parietal regions, as well as the right temporal lobe and the vermis. In the limbic and basal ganglia lobes bilaterally, and in the vermis, blood perfusion was highest in the no diagnosis group, and lowest in the cannabis-disorder group, but perfusion increased in cerebellum and occipital regions for both substance disorders. In general, in the right-lateral frontal, parietal, and temporal regions blood perfusion was highest in the cannabis-disorder group, and lowest in the no diagnosis group. Conclusion: Significant decrease in subcortical perfusion may indicate decreased motivation, concentration, and attention. Increased perfusion in the cerebellum may indicate increased baseline neural activity to maintain balance, and regulate executive function, memory, and behavior, in substance-disordered. Increased occipital activity suggests higher baseline requirements to maintain visual processing. Cannabis-disordered had greater perfusion in right-lateral frontal, parietal, and right-temporal regions, where alcohol-disordered did not, possibly due to hallucinogenic properties of cannabis having longer-lasting residual effects in the visuospatial and abstract-processing regions of the right hemisphere. The absence of significant difference across groups in the left temporal lobe may be due to lack of demand on language centers.