A comparison was made of the susceptibility of eight inbred strains of mice to infection with Trypanosoma congolense. Marked differences in susceptibility as judged by survival were found between the different strains. The capacity of certain strains to survive longer than others appeared to be related to their ability to limit the numbers of trypanosomes in the circulation. There was no difference in the infectivity of T. congolense for mice of high and low susceptibility. Furthermore, the findings of similar prepatent periods suggested that the initial replication rate was similar in the different strains. These findings suggested that the level of parasitaemia in different strains of may reflect differences in the nature of quality of the immune response to the trypanosome. In all of the strains of mice a marked increase in splenic B and null lymphocytes was found. This, allied to the finding of an increase in the background plaque-forming cells to sheep erythrocytes, indicated, as suggested by other workers, that trypanosome infection results in a non-specific polyclonal activation of lymphocytes, and that this affects primarily B lymphocytes. In strains of mice which survived longest, i.e. C57B1/6J and AKR/A, the increase in splenic B and null cells was less marked. Whether this is associated with a decreased susceptibility of these strains to polyclonal activation induced by trypanosome infection, or whether it is merely the result of lower levels of parasitaemia, remains to be determined. By comparing T. congolense infection in three strains of mice congenic at the H-2 locus, representing H-2a, H-2b and H-2k haplotypes, it was found that the susceptibility was not associated with the H-2 haplotype. The finding that (A/J X C57B1/6J)F1 hybrids were of similar susceptibility as the C57B1/6J parents indicated that the relative resistance of this strain is inherited as a dominant trait, although in the early stages of infection the F1 hybrids consistently showed somewhat higher levels of parasitaemia than the C57B1/6J mice. Athymic nude mice and surgically splenectomized mice were found to be more susceptible to T. congolense infection than intact mice of the same strain. However, the effect of splenectomy was much less pronounced in C57B1/6J mice than in the relatively more susceptible BALB/c/A mice.