Cannabis stimulates dopamine release and activates dopaminergic reward neurons in central pathways that lead to enhanced dependence. Catechol-O-methyl transferase (COMT) inactivates amplified extraneuronally released dopamine. A functional polymorphism (COMT Val158Met) resulting in increased enzyme activity has been associated with polysubstance abuse and addiction to heroin and methamphetamine. The aim of this study was to examine the relationship between the COMT Val158Met polymorphism and use of cannabis. Fifty-five cannabis users and 75 normal controls were enrolled in this study. Polymerase chain reaction-based genotyping was used to evaluate the presence of COMT gene polymorphism. There was a difference in genotype frequencies between cannabis users and controls, including the distribution of the COMT genotypes (H/H, H/L) (P < 0.001) and alleles (H, L) (P < 0.01), when comparing the patient groups and the control individuals. However, LL genotype distribution was similar between the groups. These results suggest a significant association between COMT Val158Met polymorphism and susceptibility to cannabis dependence.