It was found in our laboratory that guinea pigs on a commercial diet did not develop an Entamoeba histolytica infection of a high order and the substitution of a synthetic diet was necessary to produce a severe, fulminating type of infection. The present study was conducted in an effort to obtain some evidence as to why it has been necessary to use the synthetic diet, and to secure information as to how the diet per se influenced the development of the experimental infection. The synthetic diet was shown to cause histologic alterations in the cecal mucosa of guinea pigs which were not evident when these animals were maintained on the commercial ration. These alterations consisted of a thinning of the mucosa and a dilatation of the glandular area with vacuoles indicating secretory retention. It is postulated that the diet may have conditioned the wall of the guinea pig's cecum to permit invasion by the symbiotic amebas and bacteria. The significance of these findings is difficult to assess, but they suggest that diet, quite apart from any deficiencies, may cause tissue disturbances in specific organs for which a given parasite has an affinity, and thus predispose them to infection.