The early interaction between E. histolytica trophozoites and the intestinal mucosa was studied by light and electron microscopy using sheets of isolated epithelium of the guinea pig colonic mucosa. The integrity of the isolated epithelium was confirmed by scanning electron microscopy. After 30 minutes of interaction, the amebas adhered first, and penetrated subsecuently the epithelium of the colon at the interglandular regions. The results suggest that the trophozoites of E. histolytica invade the epithelial barrier exclusively at the regions of lowest resistence, represented by the interglandular zones of epithelial shedding.