We have used rats with epidermal growth factor (EGF) autoantibodies to study the role of EGF deficiency during perinatal development. The study was focused on organs known to contain EGF or its receptor. Compared with controls, the offspring of autoimmune rats had a higher perinatal mortality and a lower birth weight. The weight of the lungs was particularly low in the offspring of EGF-immunized rats, and morphologically the lungs from the surviving pups seemed atelectatic and had alveolar duct dilatation, which indicates mild respiratory distress syndrome. Judged from immunohistochemical studies, the amount of surfactant protein-A was decreased, suggesting a delayed lung maturation. The offspring of EGF-immunized rats had dry and wrinkled skin. The skin was thin and the hair follicles were immature. This suggests a role for EGF in the growth and development of the skin. The liver/body weight ratio was lower in pups from EGF-immunized rats. This difference was, however, not significant (p= 0.07), but flow cytometric analyses showed a significantly lower proportion of the liver cells from newborn EGF-deficient pups to be in S-phase and indicated that these cells were larger than liver cells from controls. To study possible alterations in EGF binding,125I-EGF was injected i.v. in newborn rats.125I-EGF bound in all the organs investigated. The binding is listed in decreasing order: liver, gut, skin, kidney, and lungs. In the pups from EGF-immunized rats, the lungs and the skin bound a significantly higher amount than the controls. This could represent an upregulation of the EGF receptor in response to the lack of EGF. Postnatally, the pups from EGF-immunized mothers grew faster and were on paar with controls within 1 wk. We found no differences concerning tooth eruption, ear opening, and eye opening. In extension of present knowledge concerning the tissue localization of EGF and its receptor and concerning the pharmacologic effects of EGF, our study demonstrates an effect of EGF deficiency. This supports a role for EGF in the epigenetic regulation of the development of the lungs, the skin, and the liver.