Asthma is a common disease that results from both genetic and environmental risk factors. Children attending day care in the 1st year of life have lower risks for developing asthma, although the mechanism for this ‘day care’ effect is largely unknown. We investigated the interactions between day care exposure in the 1st 6 mo of life and genotypes for 72 polymorphisms at 45 candidate loci and their effects on cytokine response profiles and on the development of atopic phenotypes in the 1st year of life in the Childhood Onset of Asthma (COAST) cohort of children. Six interactions (at four polymorphisms in three loci) with ‘day care’ that had an effect on early-life immune phenotypes were significant at P<.001. The estimated false-discovery rate was 33%, indicating that an estimated four P values correspond to true associations. Moreover, the ‘day care’ effect at some loci was accounted for by the increased number of viral infections among COAST children attending day care, whereas interactions at other loci were independent of the number of viral infections, indicating the presence of additional risk factors associated with day care environment. This study identified significant gene-environment interactions influencing the early patterning of the immune system and the subsequent development of asthma and highlights the importance of considering environmental risk factors in genetic analyses.