BALB/c mice are highly susceptible and C57BL/6 relatively resistant to Trypanosoma congolense infections. Here we show that relatively resistant wild-type B6 mice infected with T. congolense survive significantly longer (> 200 days) than infected major histocompatibility complex (MHC) class II-deficient B6 mice (∼50 days). We also show that blocking of the interleukin-10 (IL-10) receptor induces early death of wild-type B6 mice infected with T. congolense (∼10 days), but does not affect the survival of infected MHC class II-deficient B6 mice. We conclude that MHC class II-restricted immune responses mediate protection and, when IL-10 function is impaired, MHC class II-restricted immune responses mediate early mortality in otherwise resistant B6 mice. Thus, in T. congolense infections, MHC class II-restricted immune responses mediate either protection or disease, depending on IL-10 function.