Abstract Background Gene-gene and gene-environment interactions play an important role in cancer susceptibility. In this work, we studied the association of XRCC1 rs25487, ERCC1 rs735482, and CHRNA3 rs1051730 variants with lung cancer and assessed the modulatory effect of potential interaction between these variants on disease risk. Results In this study, 86 primary lung cancer patients and 64 control subjects were genotyped for CHRNA3 rs1051730, XRCC1 rs25487, and ERCC1 rs735482 by real-time PCR. The frequency of the three studied variants was higher among lung cancer patients than in control subjects, but with no statistical significance. ERCC1 rs735482 variant was associated with 6.9-fold increased risk to develop lung cancer among smokers (p = 0.03). Concomitant presence of CHRNA3 and ERCC1 wild alleles was associated with 2.7-fold elevated risk of lung cancer (p < 0.0001), while concomitant presence of CHRNA3 rs1051730 variant allele with ERCC1 wild allele was associated with 20-fold elevated risk (p < 0.000). Concomitant presence of both variants, ERCC1 rs735482 and CHRNA3 rs1051730, was associated with 9.9-fold elevated risk (p < 0.0001). Meanwhile, the concomitant presence of XRCC1 rs25487 with either ERCC1 rs735482 or CHRNA3 rs1051730 or both was not associated with increased risk of the disease. Conclusion Our results emphasize the role of gene-gene interaction in the pathogenesis of lung cancer. Large-scale further studies to clarify the underlying mechanisms are needed.