The objective of the study was to investigate the association between maternal smoking, GSTM1, GSTT1 polymorphism, low birth weight (LBW, < 2,500 g) and intra-uterine growth restriction (IUGR, < 2,500 g and gestation ≥ 37 weeks) risk. Within a prospective cohort study in Kaunas (Lithuania), a nested case-control study on LBW and IUGR occurrence among 646women with genotyping of GSTT1 and GSTM1 polymorphisms who delivered live singletons was conducted. Multivariate logistic regression analysis was used to study the association of maternal smoking and polymorphism in two genes metabolizing xenobiotics. Without consideration of genotype, light-smoking (mean 4.8 cigarettes/day) during pregnancy was associated with a small increase in LBW risk, adjusted OR 1.21; 95% CI 0.44 – 3.31. The corresponding odds for IUGR risk was 1.57; 95% CI 0.45 – 5.55. The findings suggested the greater LBW risk among light-smoking mothers with the GSTM1-null genotype (OR 1.91; 95% CI 0.43 – 8.47) compared to those with GSTM1-present genotype (OR 1.11; 95% CI 0.26 – 4.47). When both GSTM1 and GSTT1 genotypes were considered, the synergistic effect was found among smoking mothers: GSTT1-present and GSTM1-null genotype OR for LBW was 3.31; 95% CI 0.60-18.4 and that for IUGR was 2.47; 95% CI 0.31 – 13.1. However there was no statistically significant interaction between maternal smoking, GSTT1- present and GSTM1-null genotypes for LBW (OR 1.45; 95% CI 0.22 – 10.1, p = 0.66) and for IUGR (OR 1.10; 95% CI 0.10 – 12.6, p = 0.93).The results of this study suggested that smoking, even at a low-level, ought to be considered a potential risk factor for adverse birth outcomes and that genetic polymorphism may contribute to individual variation in tobacco smoke response.