Background Experimental studies suggest that glutathione S-transferase (GST) genotypes modify nasal allergen responses induced by secondhand smoke (SHS) exposure. Objective We aimed to investigate whether GSTs affected systemic IgE and allergic rhinitis (AR) in SHS-exposed individuals from a population-based cohort. Methods Analyses comprised 2309 never-smokers from the Swiss study on air pollution and health in adults cohort, reporting SHS status at baseline and 11 years later. Outcomes were defined by total serum IgE100 kU/L, specific serum IgE determined by Phadiatop(®) 0.35 kU/L and self-reported AR. GSTP1 Ile105Val, GSTM1 and GSTT1 gene deletion genotypes were identified at the follow-up survey. Results After adjustment for relevant covariates, the homozygous GSTP1 105-Val genotype was negatively associated with high total IgE and high-specific IgE by Phadiatop(®) , notably in subjects persistently exposed to SHS (OR: 0.20, 95% CI 0.05-0.75; P=0.02, for high total IgE and OR: 0.29, 95% CI 0.10-0.89; P=0.03, for high specific IgE by Phadiatop(®) ). Carrying at least one copy of the GSTM1 gene (non-null) showed a similar association for high specific IgE by Phadiatop(®) (OR: 0.41, 95% CI 0.22-0.76; P=0.004). No significant associations were found between GSTs and rhinitis. Conclusion and Clinical Relevance In this large cohort, homozygosity for GSTP1 105-Val or carrying the GSTM1 non-null genotype decreased the risk of high total IgE or high specific IgE using Phadiatop(®) by nearly half in subjects exposed to SHS, as compared with subjects carrying opposite alleles. These findings underline the value of genetic susceptibility when evaluating the effects of environmental exposure on allergic illness. The potential long-term effects of persistent SHS exposure in genetically vulnerable individuals may be of public health relevance.