Although second-hand smoke (SHS) exposure is associated with asthma, its effect on eczema is unclear. Especially, the effect of maternal passive smoking on childhood eczema has rarely been studied. Polymorphisms in tumor necrosis factor-alpha (TNF-alpha), toll-like receptor 4 (TLR4), and glutathione S-transferase P1 (GSTP1) genes interact with air pollutants and modify allergic disease development. This study aimed to investigate the effect of gene-environment interactions between SHS exposure and TNF-alpha/TLR4/GSTP1 polymorphisms on childhood eczema. From 2005 to 2006, 3,639 children aged 7 or 8 years were enrolled and followed up 2 years later. Details of SHS exposure and eczema were collected by questionnaires. TNF-alpha (rs1800629), TLR4 (rs1927911), and GSTP1 (rs1695) genotypes were determined. Maternal passive smoking during pregnancy was associated with increased prevalence of eczema diagnosis ever (adjusted odds ratio [aOR] 1.50, 95% confidence intervals [CI] 1.25-1.79), and eczema symptoms in the past 12 months (aOR 1.23, 95% CI 1.01-1.50). Persistent SHS exposure (from the prenatal period to the present) was associated with increased prevalence of eczema diagnosis ever (aOR 1.40, 95% CI 1.19-1.66). Maternal passive smoking during pregnancy and persistent SHS exposure were associated with increased risk of new eczema diagnosis in children with TNF-alpha AA or AG (aOR 2.83, 95% CI 1.11-7.23 for maternal passive smoking during pregnancy; aOR 3.65, 95% CI 1.29-10.29 for persistent SHS exposure), TLR4 CC (aOR 3.02, 95% CI 1.38-6.63 for maternal passive smoking during pregnancy; aOR 2.31, 95% CI 1.01-5.28 for persistent SHS exposure), and GSTP1 AG or GG (aOR 2.58, 95% CI 1.23-5.42 for maternal passive smoking during pregnancy; aOR 3.04, 95% CI 1.32-7.01 for persistent SHS exposure) genotypes. Interactions between SHS and TNF-alpha/TLR4/GSTP1 polymorphisms may affect childhood eczema development. Reducing SHS exposure from the prenatal period may prevent childhood eczema in susceptible populations.