Background: Dopaminergic and opioid systems are involved in mediating drug reward and reinforcement of various types of substances including psychoactive compounds. Genes of both systems have been candidate for investigation for associations with substance use disorder (SUD) in various populations. This study is the first study to determine the allele frequency and the genetic association of the DRD2 rs1076560 SNP and OPRM1 rs1799971 SNP variants in clinically diagnosed patients with SUD from the United Arab Emirates (UAE). Methods: A cross-sectional case-control cohort that consisted of 512 male subjects was studied. Two hundred and fifty patients with SUD receiving treatment at the UAE National Rehabilitation Center were compared to 262 controls with no prior history of mental health and SUD. DNA from each subject was extracted and genotyped using the TaqMan ® SNP genotyping assay. Results: There were no significant associations observed for DRD2 rs1076560 SNP, OPRM1 rs1799971 SNP, and combined genotypes of both SNPs in the SUD group. Conclusion: Further research is required with refinements to the criteria of the clinical phenotypes. Genetic studies have to be expanded to include other variants of the gene, the interaction with other genes, and possible epigenetic relationships.