Since the immune mechanisms active in response to babesiosis have not been clearly defined, the effects of antilymphocyte serum (ALS) and splenectomy on B. microti infections were assessed in immune and susceptible hamsters by degree of parasitemia, clinical course, and humoral antibody formation. In immune animals treated with ALS or splenectomy, latent infections became patent, but parasitemias during exacerbation peaked at lower levels than was the case with primary parasitemias. However, despite similar parasitemias and equivalent humoral antibody induction in both groups, seven of nine ALS-treated animals died, whereas only one of seven splenectomized hamsters died. All hamsters treated with ALS before and during primary infection died with persistent peak parasitemias and low serum titers against B. microti. Animals subjected to splenectomy before initial inoculation had an essentially normal clinical course for B. microti infection except that low levels of parasitemia persisted for many weeks and two of eight died. Splenectomized hamsters had normal humoral responses. Although cellular responses are mainly responsible for protection in babesiosis, humoral antibodies may alter the course of this disease. In view of the rather ubiquitous occurrence of Babesia spp. organisms in wild and domestic animals, this parasitosis may be more common in humans than is presently recognized, especially in immunosuppressed or splenectomized individuals and in persons with otherwise reduced cellular immune responses.