The relationships between glutathione S-transferase (GST) M1, GSTT1, and GSTP1 genotypes and acute respiratory illness were investigated in a cohort of fourth grade school children aged 9-11 years who resided in 12 southern California communities. We used respiratory illness-related absences as a measure of respiratory illness occurrence. We ascertained respiratory illness-related school absences using an active surveillance system from January 1996 through June 1996. Genotypes for GSTM1 (null versus present), GSTT1 (null versus present), and GSTP1 (Ile105Val) were determined using genomic DNA from buccal cell specimens. The effects of GST genotypes on respiratory illness were assessed using stratified absence incidence rates and Poisson regression models. GSTP1 genotype was associated with risk for respiratory illness severe enough to result in a school absence. Children who were homozygous for the Val105 variant allele had lower incidence rates of upper and lower respiratory illnesses than did children who were homozygous for the Val105 allele. Children inheriting at least one Val105 allele were protected from respiratory illnesses (relative risk, 0.80; 95% confidence interval, 0.65-0.99). GSTM1 and T1 genotypes were not associated with respiratory illness. We conclude that GSTP1 genotype influences the risk or severity of respiratory infections in school-aged children.