The early formation of amebic cecal lesions in the gerbil (Meriones unguiculatus) was studied sequentially from 1 to 10 days post-inoculation. The earliest response of the cecal mucosa towards trophozoites of Entamoeba histolytica was local release of interglandular and goblet cell mucin. Trophozoites adhered to the surface epithelium or were trapped in the luminal mucus in the absence of epithelial cell damage. Focal mucosal erosion occurred later, and was preceded by crypt hyperplasia, edema and hemorrhaging of the lamina propria. The interglandular epithelial cells were cytolysed or were sloughed off into the lumen. Amebic mucosal erosion was accompanied by trophozoite entry in the crypts, but rarely into the lamina propria. The inflammatory cellular infiltrate was diffuse, and neutrophils were found in the lumen in contact with trophozoites. The findings of this study suggest that trophozoites of E. histolytica do not actively penetrate or invade the interglandular epithelium, but rather, that amebae are permitted to invade as a result of the destruction of the epithelium. Mucus depletion and the mucosal inflammation, probably in response to the adsorption of amebic toxins, preceded epithelial erosions.