In order to obtain a better understanding of immune system dysfunction in chronic African trypanosomiasis, we have assessed primary B cell responses to helper T cell-independent and -dependent antigens in C57BL/6 mice infected with the human pathogen, Trypanosoma rhodesiense. Mean survival time of infected mice was 38 days. All animals exhibited fluctuating parasitemias until 5 to 7 days before death when parasitemias remained high. Thymus size decreased as infection progressed, but spleen size increased up to 20 X normal. The proportion of macrophages (nonspecific esterase-positive cells) and B cells or B cell progeny (Ig+) increased in spleen, whereas the proportion of T cells (θ+) decreased. However, in a terminal mouse with enlarged spleen, the absolute increase in total cell numbers reflected a 1.7 X increase in T cells, an 11.2 X increase in B cells, and a 21 X increase in macrophages compared to controls. The ability of infected mice to mount primary in vivo splenic PFC responses to helper T cell-independent antigens (SIII, PVP) was elevated throughout most of infection when compared to control animals responses; serum antibody responses to SIII or PVP paralleled the enhanced PFC responses. The terminal phase of infection was marked by a failure of B cells to respond to these antigens. The elevated primary splenic PFC responses observed during infection to T-independent antigens such as SIII may be attributed to loss of suppressor T cell control, since infected mouse spleen cells did not respond to low-dose priming with SIII. Primary in vivo B cell responses to helper T cell-dependent antigens (SRC, TNP-KLH) were initially elevated when antigen and parasites were given on the same day, but detectable primary splenic PFC responses to these antigens could not be induced after several days of infection. Suppression of PFC responses to TNP-KLH in infected mice could be completely abrogated if helper T cells were carrier-primed in animals before infection. On the basis of our studies, we suggest that intrinsic B cell function is intact and elevated throughout most of infection, but that a terminal failure of B cells precedes death. We further suggest that a loss of function of accessory and regulatory cells (helper and suppressor T cells) may be responsible for the irregularities in B cell function observed during chronic African trypanosomiasis.