Introduction Di-(2-ethylhexyl)-phthalate (DEHP) is present in a wide variety of medical devices. Infants are more susceptible than the general population. Aim of work To investigate histological and immnohistochemical changes in the lung of newborn rats in response to mothers’ exposure. Materials and methods Twenty nonpregnant adult female albino rats were used. After pregnancy, on the 15th day of pregnancy, dams were divided into two equal groups: the control group received corn oil and the treated group received DEHP (500 mg/kg/day) from the 15th day of pregnancy and during the 1st three weeks of lactation. Fifteen offspring from each group were subdivided into three subgroups, 1, 2, and 3, which were sacrificed at the 2nd, 7th, and 21st postnatal day, respectively. Lung specimens were processed for light microscope (H&E and immunohistochemical staining of proliferating cell nuclear antigen) and electron microscope examination. Results H&E-stained sections of treated lung on the 2nd day showed variable-sized saccules. Primary septa were significantly thicker than those of the control group. However, on the 7th day, focally dilated saccules with thin primary septa were observed. Saccules and secondary septa were fewer than those in the control group. On the 21st day, variable-sized alveoli and a significant increase in septal thickness were observed. Immunohistochemically, there was a significant increase in proliferating cell nuclear antigen-positive cells on both the 2nd day and the 21st day, whereas they decreased on the 7th day in comparison with the control group. Ultrastructurally, treated lung on the 2nd day showed a saccular wall with many layers of interstitial cells, some with shrunken nuclei, whereas on the 7th day, thin septa were observed. Type II pneumocytes and interstitial cells had heterochromatic shrunken nuclei, whereas on the 21st day, the presence of macrophages was observed in the lumen. Interstitials cells and type II pneumocytes showed heterochromatic nuclei and marked distortion of organelles. Conclusion DEHP induced marked histological and immunohistochemical changes in the lung. Alternative plasticizers with less adverse impact could be used. Further studies on the possible protective effect of antioxidants are recommended