Although cigarette smoking is considered a major risk factor for several human diseases, the effects of smoking on male fertility are controversial. Studies on the consequences of smoking, which also take into account genetic background, may facilitate understanding of the interactions between genes and smoking and their effects on male fertility. In this study, genetic variants of two functional polymorphisms of erythroid 2-related factor 2 (NRF2), mRNA expression levels of the antioxidant gene NRF2, catalase (CAT), superoxide dismutase isoenzyme-2 (SOD2), glutathione S-transferase-M1 (GSTM1), and seminal SOD activities were compared in 314 heavy smokers and 314 matched nonsmokers. The NRF2 rs6721961 TT genotype was found to be associated with low semen quality in heavy smokers (OR [95% CI] = 2.370 [1.106–5.081]). This variant genotype was found more frequently in heavy smokers with low semen quality than in those with high semen quality (P = 0.011). Heavy smokers with this genotype had significantly lower sperm concentrations and sperm counts (P < 0.05) when compared with those without this genotype. Smoking was also significantly associated with decreased seminal SOD activity (P < 0.05) and reduced NRF2 and SOD2 mRNA expression in heavy smokers with this variant genotype. These results were specific to heavy smokers with the NRF2 rs6721961 TT genotypes, but did not apply to nonsmokers or heavy smokers that did not carry this genotype. This study suggests an association between cigarette smoking in heavy smokers with NRF2 rs6721961 TT genotype and a decrease in semen quality.