Summary and Conclusions 1. Only three previous attempts have been reported in which the guinea-pig has been exposed to infection with Endamoeba histolytica. Two of these (Baetjer and Sellards, 1914 and Chatton, 1917) were partially successful in producing tissue invasion and one (Werner, 1908) was unsuccessful. 2. The study herein reported consisted of a planned experiment to inoculate stock guinea-pigs under strictly aseptic technic with a strain of Endamoeba histolytica of human origin. Cultured trophozoites in numbers varying from 200,000 to 7,000,000 were introduced into the terminal ileum and the animals were sacrificed in groups of five at daily intervals from one to seven days following inoculation. Six uninoculated animals served as controls. 3. On sacrifice the terminal ileum and entire large intestine were removed intact, as was the liver. The several levels were grossly inspected for suspicious amebic lesions, then these levels, designated A (terminal ileum), I (cecum), II (ascending colon), III (transverse colon), IV (descending colon) and V (rectum), were separated from one another, pH determinations made on representative animals at levels I, III and V, the fecal contents carefully studied for evidences of E. histolytica and for the natural parasites of the guinea-pig's intestine, and segments of the intestinal wall at each level fixed in Bouin's fluid, sectioned and studied microscopically. 4. The natural parasites of the guinea-pig which were identified from cecal and colonic feces were: Balantidium caviae, Chilomastix intestinalis, Trichomonas caviae, Spiromonas angusta, a Bodo-like flagellate, Eimeria caviae and once the oxyuroid nematode Paraspidodera uncinata. Except for B. caviae and Eimeria caviae, none of these organisms are tissue invaders. In no instance was there evidence that any of these organisms had assisted in the production of the amebic lesion. It was found that examination of passed fecal pellets was an unreliable method of diagnosing these infections. 5. Endamoeba histolytica was recovered from the intestinal feces in 8 of the 15 animals sacrificed on days 1–3 after inoculation, whereas typical amebic lesions were found in all 15. During days 4–7 the amebae were found in 19 of the 20 sacrificed animals and typical amebic lesions in 19, although the exceptions in each category were not coincidental. With two exceptions the lesions were confined to the cecal area; E. histolytica trophozoites were most frequently and abundantly recovered from this level but they were relatively common in the feces at levels A and II, occasionally at levels III and IV, and once at level V. The six control animals had the same natural fauna and flora found in the experimental series; in none of them were there any lesions of the intestinal wall in levels A and I–V. 6. The amebic lesions consisted of two types, (1) shallow excavations with a relatively wide diameter, and (2) deeply penetrating ones with a small orifice. Histologically some lesions consisted essentially of lytic necrosis without evidence of bacterial invasion and without host-cell reaction, and others with inflammatory reaction in which neutrophilic leukocytes and fibrocytes were predominant. 7. Amebic infection produced an appreciable increase in the pH at level I, slight increase at level III and no change at level V. 8. Spontaneous amebic lesions of the liver were found to be uncommon compared with lesions of undetermined origin observed in the guinea-pig's liver. 9. Amebiasis in the guinea-pig causes loss in weight, anorexia, reduced activity and deterioration in the appearance of the fur. 10. This study has conclusively demonstrated the high susceptibility of the guinea-pig to infection with a pathogenic strain of Endamoeba histolytica under the conditions of the experiment. It suggests the need to determine the rôle of the bacteria associated with the amebae in the inoculum, the relation of the nutritional status to susceptibility, the relative infectivity of cysts inoculated by mouth or intragastrically vs. trophozoites introduced into the terminal ileum, and possible differences in infectivity of other strains of E. histolytica.