OBJECTIVE: Substance use disorders (SUD) are among the most important public health problems throughout the world. We investigated whether COMT (Val108/158Met), CNR2 (rs2501432 and rs2229579), UCP2 (rs659366), and IL-17 (rs763780) gene variants were associated with SUD and its clinical parameters in a Turkish population. METHODS: We conducted a case-control study among 136 subjects with SUD and 100 healthy controls. Six variants were analysed by the PCR-RFLP method. RESULTS: The CNR2 rs2229579 T/T genotype and T allele increased in SUD groups than controls while the C/C genotype and C allele were more prevalent in the control group compared to the SUD group (p = 0.000 and p = 0.001, respectively). The COMT Val108/158Met Val/Val genotype and Val allele were significantly associated with polysubstance abuse (p < 0.05). There was no significant difference between the SUD group and control group regarding genotype and allele frequencies of COMT (Val108/158Met), CNR2 (rs2501432), UCP2 (rs659366) and IL-17 (rs763780) variants. CONCLUSIONS: This is the first study that discussed the relation of these variants and SUD patients in the Turkish population. The results of the analysis indicated that the CNR2 rs2229579 variant has an effect on susceptibility to SUD, suggesting that this variant might play a role in the physiopathology of SUD. The COMT Val108/158Met variant might be an important factor affecting polysubstance use.