BackgroundComorbidity of eczema withith autism spectrum disorder (ASD) is increasing. We investigated the associations of eczema and its possible interaction with polymorphisms in glutathione S-transferase (GST) genes in relation to ASD and ASD severity. MethodUsing data from 344 1:1 age- and sex-matched ASD cases and typically developing controls, we assessed additive and interactive associations of eczema with GST genes in relation to ASD by applying conditional logistic regression models, and in relation to ASD severity in ASD cases as measured by the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2) total and domain-specific comparison scores (CSs) by fitting general linear models. ResultsAfter adjusting for child’s age and history of breastfeeding, eczema had no additive association with ASD [Matched Odds ratio (MOR) and 95 % Confidence Intervals (CI): 1.04 (0.76, 1.41), P = 0.82] or ASD severity (all P > 0.20). Using a recessive genetic model, eczema was significantly associated with ASD only among children with the Val/Val genotype for the GSTP1 Ile105Val polymorphism [MOR (95 % CI) = 2.04 (1.02, 4.08), P = 0.04, P for interaction = 0.03]. In addition, among ASD cases with the GSTM1 DD genotype, those with eczema had a marginally significant higher mean ADOS-2 Social Affect CS than those without eczema (7.3 vs. 6.8, P = 0.08, P for interaction = 0.09). ConclusionOur findings suggest children with certain genotypes for GST genes may be more susceptible for comorbidity of eczema and ASD, which is consistent with the role of GST genes in both conditions.