Objective: The purpose of this study was to investigate whether functional variants of Catechol-O-Methyltrans-ferase (COMT) (rs4680) and Cannabinoid Receptor 2 (CNR2) (rs2501432) genes play a role in tobacco use disor-der (TUD) or tobacco use disorder and schizophrenia (TUDSch) comorbidity. Methods: This study consisted of 163 participants with TUD, 60 participants with TUDSch, and 106 gender-, age- and ethnicity-matched non-smoker con-trols (HNC). While the TUD and TUDSch were diagnosed according to the DSM-5, the severity of TUD was rated according to the Fagerstrom Test for Nicotine Dependence. Genotyping of COMT and CNR2 genes was determined using the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Results: Distributions of genotypes and allele frequencies were compared among the groups. Patients with TUDSch had higher frequency of COMT Val/Val genotype compared to the TUD and HNC groups (p=0.001, p=0.034, respect-tively). Patients with TUD had higher frequency of Val/Met genotype than TUDSch and HNC groups (p=0.001, p=0.033, respectively). The frequency of the Val allele was higher in TUDSch than the HNC group, whereas the frequency of the Met allele was higher in TUD than in the TUDSch group (p=0.047, p=0.001, respectively). Addi-tionally, patients with TUD had higher frequency of TT CNR2 genotype than the HNC group (p=0.019). Conclusion: While the Val/Val genotype of the COMT gene is associated with an increased risk for TUDSch, the Val/Met geno-type is associated with an increased risk for TUD. Additionally, the TT CNR2 genotype was associated with in-creased risk for TUD in the Turkish population. [Anadolu Psikiyatri Derg 2020; 21(6.000): 572-578]