Background: High genetic risk (HR) of atopy among unstratified populations of infants is associated with attenuated IFN-gamma responses. However, the role of IFN-gamma in progression from HR status to active disease is less clear.Objective: To identify immune function markers in neonates with HR that are associated with positive atopic outcomes at 2 years.Methods: Cord blood mononuclear cells (CBMCs) were collected from 175 children with HR and cryopreserved. The children were assessed for atopy by skin prick at 0.5 and 2 years. CBMCs were thawed and stimulated with allergens and mitogens PHA and staphylococcal enterotoxin B (SEB), and cytokine responses were determined.Results: No correlations were observed between allergen specific CBMC responses and atopic outcomes. In contrast, sensitization was strongly associated with polyclonal IFN-gamma responses to both PHA (P=.002) and SEB (P =.005), and also with SEB-induced IL-5 (P=.05), IL-10 (P =.02), and IL-13 (P =.01). Logistic regression analysis identified elevated PHA-induced IFN-gamma and SEB-induced IL-13 responses as the strongest independent predictors of atopy development. Cell separation studies confirmed CD8(+) T cells as the source of similar to90 % of IFN-gamma production.Conclusions: IFN-gamma produced by CD8(+) T cells may synergize with T(H)2 cytokines in driving atopy development in children with HR.