Objective.Recent studies have identified signal transducer and activator of transcription 4 (STAT4) as a susceptibility gene for systemic lupus erythematosus (SLE) in different populations. Similarly, tumor necrosis factor receptor superfamily, member 1B (TNFRSF1B) has been reported to be associated with SLE risk in Japanese populations. Along with environmental factors such as smoking, both polymorphisms may modulate an individual’s susceptibility to SLE. We investigated these relationships in a case-control study to evaluate risk factors for SLE among Japanese women.Methods.We investigated the relationship of theSTAT4rs7574865 andTNFRSF1Brs1061622 polymorphisms to SLE risk with special reference to their combination and interaction with cigarette smoking among 152 SLE cases and 427 controls.Results.The TT genotype ofSTAT4rs7574865 was significantly associated with increased risk of SLE (OR 2.21, 95% CI 1.10–4.68). Subjects with at least one G allele ofTNFRSF1Brs1061622 had an increased risk of SLE (OR 1.56, 95% CI 0.99–2.47). The attributable proportion due to the interaction between theTNFRSF1Brs1061622 genotypes and smoking was estimated to be 0.49 (95% CI 0.07–0.92), indicating that 49% of the excess risk for SLE in smokers with at least one G allele was due to an additive interaction. A lack of significant associations ofSTAT4with smoking was observed. No significant gene-gene interactions were found among polymorphisms ofSTAT4andTNFRSF1B.Conclusion.Our findings suggest that the association between cigarette smoking and SLE could be differentiated by theTNFRSF1Brs1061622 T allele among female Japanese subjects. This preliminary exploratory result should be confirmed in a larger study.