Our aims were to assess association of dichlorodiphenyldichloroethylene (DDE) with childhood asthma measured up to age 6 and the effect of DDE on the protective effect of breastfeeding on asthma. In addition, we attempted to assess the relevant time-window of DDE exposure (i.e. at birth or at 4 years). All women presenting for antenatal care in Menorca, Spain over a 12-month period beginning in mid-1997 were invited to take part in a longitudinal study that included a yearly visit. Four hundred eighty-two children were enrolled and 462 provided complete outcome data after 6.5 years of follow-up. Organochlorine compounds were measured in cord serum of 402 (83%) infants and in blood samples of 285 children aged 4. We defined asthma as the presence of wheezing at age 6 and during any preceding year or doctor-diagnosed asthma, and used skin prick test at age 6 to determine atopic status. Results At birth and 4 years of age, all children had detectable levels of DDE (median 1 ng/mL and 0.8 ng/mL, respectively). From birth to age 4, the mean DDE level among children with artificial feeding decreased by 72%, while among breastfed children it increased by 53%. Diagnosed asthma and persistent wheezing were associated with DDE at birth [odds ratio (OR) for an increase in 1 ng/mL, OR=1.18, 95% confidence interval (95% CI)=1.01-1.39 and OR=1.13, 95% CI=0.98-1.30, respectively], but not with DDE at 4 years. Neither breastfeeding nor atopy modified these associations (P>0.3). Breastfeeding protected against diagnosed asthma (OR=0.33, 95% CI=0.08-0.87) and wheezing (OR=0.53, 95% CI=0.34-0.82) in children with low and high DDE levels at birth. Conclusion In a community without known dichlorodiphenyltrichloroethane environmental releases, this study strengthens the evidence for an effect of DDE on asthma by measuring the disease at age 6 and does not support the hypothesis that DDE modifies the protective effect of breastfeeding on asthma.