The adenoviral E1A proteins possess the ability to associate with the DNA binding domains of a number of transcription factors, and in this manner promiscuously to activate a wide variety of genes. The present study was designed to determine whether this protein is expressed in human lungs where nonlytic adenoviral infection has been demonstrated. Lung tissue from 12 patients harboring trace amounts of viral DNA were examined along with A549 cells infected with adenovirus 5 and uninfected Graham 293 (G293) cells as controls. Immunohistochemical staining was used to identify E1A proteins. The control studies examined both types of cultured cells either grown on coverslips, as cryosections of cells embedded in blocks, and or as formalin-fixed, paraffin-embedded sections. E1A proteins were detected in all three control preparations in both types of cells and were detected in the nucleus of adenovirus 5-infected A549 cells 4 h postinfection. Generally, all preparations of infected A549 cells showed greater of staining than the corresponding preparation of G293 cells. Formalin-fixed, paraffin-embedded cells gave the best morphology. Immunolabeling for adenovirus E1A proteins was also demonstrated in six of 12 paraffin-embedded lung samples. We conclude that adenovirus E1A proteins are expressed in human lung tissue and speculate that they may contribute to the pathogenesis of chronic obstructive pulmonary disease by amplifying the airways inflammation associated with cigarette smoking.