OBJECTIVE: The role of DNA repair mechanisms has received attention recently in schizophrenia (Sch). Sch patients show an increased prevalence of nicotine dependence (ND). This study aimed to find out whether functional SNP variants in the XRCC1 and the XPD play any role both in ND and Sch + ND etiopathogenesis in a Turkish population which was followed up with an in silico analysis approach. METHODS: XRCC1 rs25487 and XPD rs13181 variants were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In the prediction of pathogenic effect of rs25487 and rs13181 SNPs, the PANTHER and SNPs&GO programs were used. Also, the protein-protein interaction analysis was performed to retrieve functional partners of the XRCC1 and XPD protein. RESULTS: XRRC1 rs25487 GG genotype was significantly lower in both ND and Sch + ND groups than the controls (p = .001, p = .006) while G allele was lower only in Sch + ND group comparison to controls (p = .034). XPD rs13181 Lys/Lys genotype was more lower in both Sch + ND and ND groups than in controls (p = .007; p = .001). XPD rs13181 Gln allele was lower in Sch + ND group compared to controls while Lys allele was higher in ND group than controls, respectively (p = .034; p = .008). The results of in silico prediction analysis showed that the rs25487 had neutral effect while the rs13181 had a disease-related effect. CONCLUSIONS: The results of the current study revealed a possible genetic association between XRCC1/XPD variants and both in ND and Sch + ND. We think that analysis of this missense SNPs using bioinformatics methods would help diagnosis of XRCC1 and XPD-related diseases.