Background: Air pollutants induce the increase of inflammatory components in the lungs and the decrease in pulmonary function. Genetic polymorphisms may modify the inflammatory and immunological response to the inhalation of those pollutants. Objective: To investigate effect modification by GST and TNF-α polymorphisms in the association between particulate matter (PM10) and lung function. Methods: This is a cross-sectional epidemiological study with 112 asthmatic children aged 6 to 14 years old. GSTM1, GSTT1, GSTP1, and TNF-α polymorphisms were genotyped using the polymerase chain reaction (PCR) technique. Spirometry tests were conducted. We tested associations using generalized linear models, adjusting for confounding variables. The effect modification of the genetic polymorphisms was assessed, including the genotypes and pollutants. Results: In carriers of the TNF-α-308 GA or AA genotypes, we found a reduction of 11.5% (95% CI: -19.08, -3.30) in FEV1 in the current exposure to PM10 and a reduction of 10.46% (95% CI: -14.91, -5.77) for the 5-day cumulative exposure. The TNF-α-1031 TT genotype was associated with a decline in FEV1 and FEF25-75% for the cumulative exposure to PM10. The GSTP1 wild-type genotype was associated with a decrease in FEF25-75% of 23.45% (95% CI; -30.6, -15.56) and in FEV1 of 13% (95% CI; -15.21, -10.74). We found that among GSTT1 null children, the cumulative exposure to PM10 was also associated with a reduction in FEV1, FVC, and FEF25-75%. Conclusion: Genetic polymorphism in GST and TNF-α may modify the association between particulate matter and pulmonary function in asthmatic children and adolescents.