The host immune system has been documented to influence the course and outcome of infection with the phospholipase-C-deficient (PLC^-/-) Trypanosoma brucei brucei. We addressed the resistant mechanisms during trypanosomosis by comparing the immune response to variant-specific surface glycoprotein (VSG) in relatively susceptible C3H mice and trypanotolerant (C57BL/6 × BALB/c)-F1 (B6B-F1) mice infected with PLC^-/- parasites. During the early stage of infection, lymphoid cells from both PLC^-/--susceptible C3H and -tolerant B6B-F1 mice mainly secreted VSG-specific IFN-γ. Although C3H mice remained locked in a type-I cytokine environment (IFN-γ, TNF-α) during late stage of infection, B6B-F1 mice switched to production of type-II cytokines (IL-4, IL-10) from late stage of infection onwards. It seems that VSG-specific cytokine responses associated with resistance to murine African trypanosomosis are infection-stage dependent, with type-I cytokine responses being critical during the early stage of infection while type-II cytokine responses appear to be more important during the late and chronic phases of the disease. Because of the striking similarities in the course of the PLC^-/-infection in B6B-F1 mice with that of the trypanotolerant N'dama cattle naturally-infected with T. congolense, the PLC^-/--infected B6B-F1 mice represents a suitable model to study the course of infection and immune responses during bovine trypanosomosis.