The time course and nature of mucosal damage induced in rabbit ileal loops by two strains of Salmonella typhimurium (TML and W118) isolated from human infections was assessed by immunofluorescence microscopy and by scanning and transmission electronmicroscopy. Salmonella-induced fluid secretion occurred in the presence or absence of gross mucosal architectural damage. Neither strain caused mucosal ulceration. When damage did occur, the villi were shortened by loss of their tip regions with concomitant reforming of an intact mucosal surface. Immediately preceding the onset of fluid secretion, marked infiltration of the mucosa with polymorphonuclear leukocytes and occasional macrophages was seen. This revives an earlier suggestion that interaction between invading salmonellae and acute inflammatory cells may be an important factor in initiation of fluid secretion. Brush-border invasion by salmonellae cannot per se be the immediate cause of fluid secretion, because the latter occurred several hours after initial invasion.