Apoptosis is important for targeting cancer cells for destruction. Various single-nucleotide polymorphisms (SNPs) in apoptotic genes have been associated with increased risks in lung cancer, particularly FAS -1377 G>A (rs2234767), FASLG -844 C>T (rs763110), IL1B +3954 C>T Phe105Phe (rs1143634) and BAT3 Ser625Pro (rs1052486). We studied the association of these SNPs with non-small cell lung cancer (NSCLC) in a large case-control study (N = 4263: 2644 cases and 1619 controls). No associations with NSCLC were observed in the main effects analysis for all four SNPs, adjusting for age, gender, smoking status, pack-years and years since smoking cessation. In subjects under age 60, for FASLG -844 C>T polymorphism, CT compared with the CC genotype, was significantly associated with increased risk of NSCLC, adjusted odds ratio (aOR) = 1.58 (1.22, 2.05), P = 0.0006 and TT aOR = 1.45 (1.01, 2.04), P = 0.04. In contrast, for those over age 60, the CT aOR = 0.91 (0.73, 1.13), P = 0.37 and TT aOR = 0.86 (0.64, 1.16), P = 0.32. The P-value for the age-genotype interaction was 0.004. For the IL1B +3954 C>T polymorphism, compared with the CC genotype, TT showed significant associations in former smokers and in men but tests of interaction were not significant (P(smoking) = 0.24, P(gender) = 0.17). No interactions were observed for FAS -1377 G>A and BAT3 Ser625Pro polymorphisms. Our findings indicate that age and smoking may modify the association of the FASLG -844 and IL1B + 3954 SNPs with the risk of NSCLC.