Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase (NQO1) and glutathione S-transferase (GST) M1 are phase II enzymes important in response to oxidative stress, such as occurs during exposure to ozone. We examined the relationship between functionally significant polymorphisms in NQO1 (Pro187Ser) and GSTM1 (homozygous deletion) and asthma risk in children with high lifetime exposure to ozone. We enrolled children with asthma from the allergy referral clinic at a public pediatric hospital in Mexico City, together with their parents. We assayed for the Pro187Ser polymorphism in NQO1 using a polymerase chain reaction-restriction fragment length polymorphism assay and for the presence of GSTM1 by polymerase chain reaction among 218 case-parent triads. We did not find strong evidence of an association between NQO1 genotype alone and asthma risk. However, among subjects with homozygous deletion of GSTM1, carriers of a serine allele were at significantly reduced risk of asthma compared with Pro/Pro homozygotes (relative risk = 0.4; 95% confidence interval, 0.2-0.8). The p value for difference in relative risk for NQO1 by GSTM1 genotype = 0.013. These data are consistent with a protective effect of the NQO1 Ser allele in this population of GSTM1-null children with high ozone exposure.