Delayed-type hypersensitivity (DTH) to live or fixed Entamoeba histolytica was induced and compared in mice and hamsters. Peak reactions were obtained 24 h post-challenge. In mice, challenge with 105 amoebae produced maximal, specific footpad swelling; in hamsters, 5×104 were required. Elicitation of DTH in mice was strongest 1 week after induction and remained comparatively high for 8 weeks. In hamsters, elicitability declined after 1-2 weeks. Cyclophosphamide increased footpad reactions in mice and hamsters when given 1 day prior to induction but not prior to challenge. Reactions were usually somewhat (but not significantly) stronger in mice than in hamsters, which was also evident from adoptive transfer experiments. Thus, differences in cell-mediated immunity as expressed by DTH in mice and hamsters do not explain the differential susceptibility of these animals to infection with this parasite. In hamsters, multiple footpad injections of live or fixed amoebae lowered the percentage of subsequent liver infections after i.p. injection of virulent amoebae.