The tumor suppressor protein p53 (TP53) plays a central role in directing cellular responses to DNA damage. Tumor protein 53-binding protein 1 (TP53BP1) binds to TP53 and has a potential role in DNA damage responses. DNA damage-dependent interaction between TP53 and TP53BP1 may contribute to lung cancer risk. We aimed to assess whether or not TP53 and TP53BP1 genetic polymorphisms modulate lung cancer susceptibility in a Japanese population. We investigated the relationship of the TP53 Arg72Pro and TP53BP1 Asp353Glu polymorphisms to lung cancer risk with special reference to polymorphism-polymorphism and polymorphism-smoking interactions among 462 lung cancer cases and 379 controls. The Glu/Glu genotype of TP53BP1 Asp353Glu polymorphism was associated with a decreased risk of lung cancer [odds ratio (OR) = 0.46, 95% confidence interval (CI) = 0.29-0.74]. There was no polymorphism-smoking interaction. A combination of the Pro allele carriage of the TP53 Arg72Pro polymorphism and the Glu/Glu genotype of the TP53BP1 Asp353Glu polymorphism was associated with a decreased risk of lung cancer (OR=0.38, 95% CI=0.17-0.83). The multiplicative interaction measure was statistically significant (OR for interaction = 2.93, 95% CI=1.24-6.93). The relative excess risk due to interaction and attributable proportion due to interaction were 0.74 (95% CI=0.38-1.20) and 0.63 (95% CI=0.05-1.21), respectively. Both the additive interaction measures were not equal to zero, suggesting that the existence of a biological interaction. Our findings indicate the possible association of the Glu allele of the TP53BP1 Asp353Glu polymorphism with lower risk of lung cancer especially among the Pro allele carriers of the TP53 Arg72Pro polymorphism.