In epidemiological studies of respiratory syncytial virus (RSV) disease, breast milk has proven to be beneficial. However, a host mechanism that is associated with both disease severity and that is capable of being modulated by breast milk, has not yet been identified. Both the predominance of interleukin-10 (IL-10) over interferon-gamma (IFN-gamma), and high soluble interleukin-2 receptor antagonist (sCD25) concentrations have been associated with RSV severity. We explored if they were modulated by breastfeeding. Previously healthy Chilean infants from Santiago with RSV infection (n = 349) were consecutively enrolled in the study if they were term births, without underlying pathology. Breastfeeding was described as absent or present, and if partial or exclusive. Immune response was expressed through plasma concentrations of IFN-gamma, IL-10 and sCD25, obtained both in the acute and the recovery phase. The acute phase sCD25 concentrations were lower in the breastfed (13.8 ng/mL, n =133), compared with the non-breastfed infants (15.9 ng/mL, n 27, p = 0.015). The difference increased in infants below 3 months of age (p = 0.006) and with exclusive (p = 0.004), compared to partial breastfeeding (p = 0.025). When analyzed together with age, sex, severity and environment, breastfeeding was the only independent predictor of high sCD25 concentrations (above mean + 1SD, OR 4.6, 95% CI 1.8-11.9, p = 0.0015). The recovery phase IFN-gamma/IL-10 ratio was higher in the breastfed infants, but when analyzed with potential confounding factors, only female sex was associated with an increased ratio (OR 2.32, 95% CI 1.02-5.29, p = 0.045). High sCD25 concentrations during the acute phase of infection, previously associated with severe RSV disease, were significantly and independently reduced in association with breastfeeding, whereas the Th1/Th3 balance was only modified in the recovery phase.