Axenically grown pathogenic and non-pathogenic isolates of Entamoeba histolytica have been shown to adhere to mammalian epithelial cells and bacteria by virtue of carbohydrate-binding proteins present on their cell surfaces. The interaction of amoeba isolates of low pathogenicity with a variety of gram-negative bacteria, mainly Escherichia coli strains which are readily ingested by the amoebae after relatively short periods, significantly increased the ability of the trophozoites to: (a) destroy and ingest intestinal epithelial cells; (b) secrete a cytopathic substance which morphologically affects a variety of tissue-cultured cells; and (c) cause hepatic abscesses in hamsters. Addition of carbohydrates that inhibit the lectin-mediated attachment of bacteria to amoebae prevented the enhancement of virulence. Interaction of the amoebae with bacteria that were heat-inactivated, glutaraldehyde-fixed or disrupted by sonication, as well as with bacteria precoated with antibodies or concanavalin A, did not lead to an increase in virulence. Moreover, short prior treatments of the bacteria with inhibitors of protein synthesis, but not with cell-wall synthesis inhibitors, also prevented the stimulation. The results indicate that interactions of amoebae with certain bacteria may be responsible for the increase in amoebic virulence.