Epidermal growth factor (EGF) is a potent mitogen for a variety of eukaryotic cells. EGF is found in a number of tissues and is prevalent in necrotic tissues and granulomata. The biological effect of EGF on mammalian cells is initiated by the binding to a specific receptor. Both Mycobacterium avium and Mycobacterium tuberculosis cause lung infections and localized or disseminated disease in both patients without AIDS and those with AIDS. Histopathologic studies show necrosis in the lung, liver, and splenic tissues of patients with disseminated mycobacterial infection. In the course of experiments to examine the effect of growth factors on macrophages, it was observed that M. avium and M. tuberculosis but not Mycobacterium smegmatis cultured in the presence of 5, 50, or 500 ng of EGF per ml grew significantly faster than mycobacteria cultured in the absence of EGF. 125I-EGF was found to bind to M. avium and M. tuberculosis, and the binding was competitively inhibited by unlabeled EGF. A receptor for EGF was identified on mycobacteria. Incubation of mycobacteria with EGF prior to infection of macrophage monolayers resulted in faster bacterial growth within macrophages compared with that of mycobacteria not incubated with EGF. EGF-binding protein was cloned and expressed in Escherichia coli, and subsequently the protein was purified and the N-terminal amino acids were sequenced. These results suggest that EGF is a growth factor for pathogenic mycobacteria in granulomatous tissues and within macrophages and might enhance growth rates of both intracellular and extracellular mycobacteria in the site of infection.