Background: Exposure to allergens early in life influences the development of allergen-specific immune responses. In animal models, the development of tolerance to proteins delivered to the gastrointestinal and the respiratory mucosa is influenced by age and genetic background. Late introduction of cow’s milk in infants is associated with slower increase and lower peak IgG antibody responses to milk during early childhood, but the long-term effects have not been investigated, nor is the relation to atopic disease later in life clear. Objective: The purpose of this study was to investigate the development of IgG subclass antibodies to β-lactoglobulin in relation to early exposure to cow’s milk, atopic heredity, and the development of atopic disease. Methods: IgG subclass antibodies to β-lactoglobulin were analyzed by ELISA at birth, at 6 and 18 months, and at 8 years in 96 children followed prospectively. Results: The levels of IgG subclass antibodies to β-lactoglobulin peaked in early childhood and then declined up to 8 years of age. Exposure to cow’s milk during the first 3 months of life was associated with high IgG subclass antibody levels to β-lactoglobulin up to 8 years, particularly in children with maternal atopy. Children with atopic symptoms and sensitivity to allergens often had high levels of IgG₄ antibodies to β-lactoglobulin at 8 years of age, even if they were not exposed to cow’s milk during the first 3 months of life. Furthermore, atopic dermatitis was associated with high levels of IgG subclass antibodies to β-lactoglobulin in early childhood. Conclusions: IgG subclass antibody levels to milk peak during early infancy, with particularly high levels in children with atopic dermatitis, and decline thereafter. Exposure to cow’s milk during early infancy has long-lasting effects on the humoral antigen-specific responses, indicating less effective tolerance-inducing mechanisms in the intestinal mucosa during the first months of life. (J Allergy Clin Immunol 1998;102:671-8.)