C3HeB/FeJ (C3H) mice infected ip with 106, 5 × 105, and 105 blood-form trypomastigotes (BFTs) of the Y strain of Trypanosoma cruzi were more resistant than C57B1/6 (B6) mice infected in the same manner. This pattern of susceptibility is opposite that reported for other stocks of this parasite. In a second experiment, C3H and B6 mice were infected ip or sc with 2 × 106, 106, 5 × 105, 105, or 103 Y strain BFTs. C3H mice infected ip with the 3 highest doses were again more resistant than the B6 mice, while mice infected ip with the 2 lowest doses were essentially equivalent in resistance. Thus, the difference in susceptibility was detectable, in terms of parasitemia levels and survival, primarily at the higher infection doses. For the groups infected sc, the pattern of susceptibility reversed. B6 mice infected with the 3 highest doese had lower parasitemia levels than the corresponding C3H mice, while C3H and B6 mice infected with 105 or 103 BFTs were similar in resistance. Blastogenic responses of lymphoid cells to phytohemagglutinin (PHA) and a soluble trypanosome extract (STE) were compared for C3H mice infected ip or sc to determine if the susceptibility to infection obtained with the 2 routes would be associated with differences in immune responses. Mesenteric lymph node cells (MLNCs) of mice infected ip were responsive to the STE early in infection, while superficial lymph node cells (SLNCs) of these mice were not. C3H mice infected sc had SLNCs which yielded strong responses to STE, while their MLNCs were relatively unresponsive. PHA stimulated responses by lymphoid cells from mice infected ip or sc were similar. Also, mice infected ip and sc produced equivalent levels of IgG, IgM, and IgA parasite specific antibodies, as detected by an ELISA.