The relationships between course of infection, antigenic variation, and immunodepression of antibody responses to heterologous antigens have been investigated in mice chronically infected with Trypanosoma brucei. T. brucei Brunel University Trypanosomiasis (BUT) 64 produces a fluctuating parasitaemia lasting about 80 days and ending fatally. It is demonstrated that recurring peaks of parasitaemia are associated with the appearance of new variant antigenic types. At 21 and 31 days of infection, IgG responses to the heterologous antigen, sheep red blood cells (SRBC), are absent and IgM responses are less than 5% of normal. When a single dose of cyclophosphamide (300 mg/Kg) was injected into mice on day 31 of infection, the parasitaemia rose sharply in an uncontrolled fashion and the treated mice died in about 10 days. Cyclophosphamide, given in this way, is known to ablate antibody production completely but temporarily. It is therefore concluded that even though infected mice make extremely poor antibody responses to heterologous antigens, they are still capable of producing sufficient antibody to control peaks of parasitaemia associated with the emergence of new variant antigenic types. The significance of these findings is discussed in relation to recurrent hypotheses of trypanosome-associated immunodepression.