BACKGROUND:Glutathione S-transferase (GST) genes are involved in the management of oxidative stress in the lungs. We aimed to determine whether they modify the associations between early life smoke exposure and adverse lung health outcomes. METHODS:The Melbourne Atopy Cohort study (a high-risk birth cohort) enrolled 620 children and followed them prospectively from birth. We recorded perinatal tobacco smoke exposure, asthma, and lung function at 12 (59%) and 18 years (66%) and genotyped for GSTM1, GSTT1, and GSTP1 (69%). RESULTS:GST genotypes were found to interact with tobacco smoke exposure on lung function outcomes (P interaction ≤ .05). Only among children with GSTT1 null genotypes was exposure to mother's, father's, or parental tobacco smoke in early life associated with an increased risk of reductions in prebronchodilator (BD) FEV1 and FVC at both 12 and 18 years. These associations were not seen in children with GSTT1 present. Similarly, only among children with GSTM1 null genotypes was exposure to father's or parental smoking associated with reductions in pre- and post-BD FEV1 and FVC at 18 years. Only among children with Ile/Ile genotypes of GSTP1 was exposure to mother's smoking associated with increased risk of reduced FEV1 at 18 years, but this was not the case among children with Val/Val or Ile/Val genotypes. CONCLUSIONS:Our study provides evidence of interaction between early tobacco smoke exposure and GST genotypes on lung function. Carriers of GST null mutations and GSTP1 Ile/Ile alleles may be more susceptible when exposed to tobacco smoke in early life. These findings support stronger recommendations to protect all infants from tobacco smoke exposure. TRIAL REGISTRY:Australian and New Zealand Clinical Trials Registry; No.: ACTRN12609000734268; URL: http://www.anzctr.org.au/.