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Evidence suggests that smoking adversely affects bones. Glutathione S-transferases (GSTs) are important in the detoxification of tobacco smoke compounds. This study investigated the influence of GSTM1 and GSTT1 genetic polymorphisms on the effects on bone induced by tobacco smoking in young men. In total, 231 Chinese men aged 20-39 years were assessed by a cross-sectional study. Calcaneal quantitative ultrasound (QUS) was measured. Smoking information was obtained using a questionnaire. Genotypes were determined for null alleles of GSTM1 and GSTT1. Smoking was inversely associated with speed of sound (SOS) and bone quality index (BQI) among subjects with GSTM1 null genotype (β = -0.28, 95% CI, -34.01 to -8.65 and β = -0.30, 95% CI, -16.41 to -4.49, respectively), but not among those with the allele present (β = -0.02, 95% CI, -15.01 to 12.59 and β = -0.09, 95% CI, -8.75 to 3.02, respectively). P for interaction = 0.04 for SOS and 0.08 for BQI. No interaction was found between the GSTT1 polymorphism and smoking. The results showed that GSTM1 deficiency may increase the adverse effect of smoking on calcaneal QUS in young men, suggesting an interaction between metabolic genes and tobacco smoke in bone detoxification.