OBJECTIVE To investigate whether specific IgA, IgG, IgG1 and IgG4 responses to cow's milk proteins differ between infants with cow's milk allergy and infants with cow's milk related symptoms (control subjects), and whether early feeding affects these responses as well as specific IgE. METHODS A cohort of 6,209 healthy, full-term infants in a double-blind randomized trial received, as supplementary feeding at maternity hospitals (mean duration 4 days), either cow's milk formula, extensively hydrolyzed whey formula or donor breast milk. Infants who developed cow's milk associated symptoms (n = 223) underwent an open oral cow's milk challenge (mean age 7 months), which confirmed cow's milk allergy in 111 and was negative in 112. We measured in sera cow's milk specific IgE levels with UniCAP (Phadia, Uppsala, Sweden), and β-lactoglobulin and α-casein specific IgA, IgG1, IgG4 and IgG levels with enzyme-linked immunosorbent assay. RESULTS Infants with IgE-mediated cow's milk allergy had lower β-lactoglobulin and α-casein specific IgG1, IgG4 and IgG levels (p < 0.05) than infants with non-IgE-mediated cow's milk allergy or control subjects. Within the group of infants with cow's milk allergy, exposure to cow's milk during the first few days after birth led to higher β-lactoglobulin and α-casein specific IgG4 levels (p < 0.005) compared to infants fed with either breast milk or extensively hydrolyzed formula. CONCLUSIONS Subdued IgG class responses to cow's milk proteins characterized IgE-mediated cow's milk allergy. In infants who developed cow's milk allergy early exposure to cow's milk resulted in a heightened specific IgG4 response.