Resistance to intestinal amoebiasis is mouse strain dependent. C57BL/6 (B6) mice clear Entamoeba histolytica within hours of challenge, whereas C3H and CBA strains are susceptible to infection and disease. In this study, we show using bone marrow (BM) chimeric mice that mouse strain-dependent resistance is mediated by nonhemopoietic cells; specifically, B6 BM→ CBA recipients remained susceptible as measured by amoeba score and culture, whereas CBA BM→ B6 recipients remained resistant. Interestingly, hemopoietic IL-10 was required for maintaining the resistance of B6 mice, in that B6 IL-10-deficient mice and IL-10−/− BM→ wild-type recipients, but not IL-10+/+ BM→ IL-10−/− recipients, exhibited higher amoeba scores than their wild-type controls. Additionally, C57BL/10 IL-10−/− Rag2−/− mice exhibited diminished amoeba scores and culture rates vs IL-10−/− mice, indicating that lymphocytes potentiated the susceptibility of IL-10-deficient mice. We conclude that nonhemopoietic cells mediate the natural resistance to intestinal amoebiasis of B6 mice, yet this resistance depends on hemopoietic IL-10 activity.