The role of the epidermal growth factor (EGF) receptor in cell invasion by Salmonella typhimurium was examined in vitro and in vivo by using waved-2 mice which express an EGF receptor with reduced kinase activity. S. typhimurium invaded fibroblasts from waved-2 mice as efficiently as fibroblasts from wild-type control animals. In vivo, S. typhimurium both invaded the gastrointestinal tract and penetrated through to the spleen of waved-2 mice. Our studies suggest that the EGF receptor has only a limited role, if any, in cell invasion by S. typhimurium.