The infection by a non-lethal strain of Plasmodium yoelii induces the formation of autoantibodies such as anti-DNA and anti-Sm antibodies in mice. The extent of the relative increase in serum levels of IgM and IgG anti-DNA and anti-Sm antibodies and their kinetics were found to be similar to those of anti-hapten antibodies and of total IgM and IgG levels. This strongly suggested that anti-DNA and anti-Sm autoantibody responses observed in malaria-infected mice are a result of polyclonal activation of B cells. The analysis of the IgG subclasses reacting with DNA antigen showed significant levels of the T cell-dependent isotypes, IgG1 and IgG2. The role of T cells in the activation of autoreactive B cells was confirmed by using athymic nude mice. Indeed, BALB/c-nu/nu and C57BL/6-nu/nu mice failed to produce IgG anti-DNA antibodies after infection with P. yoelii. Moreover, the reconstitution of BALB/c nude mice with lymph node cells from congenic euthymic BALB-Igb mice showed the activation of autoreactive B cells in nude mice by T cells from euthymic mice. Studies in mice depleted of CD4+ T cells strongly suggested that malaria-induced anti-DNA antibodies were almost entirely dependent on the presence of CD4+ T cells, as this depletion significantly decreased IgM anti-DNA antibodies and completely abolished the IgG anti-DNA production, including the IgG3 subclass in infected mice. In contrast, depletion of the CD8+ T cell subset had no effect on the production of autoantibody in malaria-infected mice. Our results indicate that CD4+ T cells play a major role for both IgM and IgG anti-DNA production during the course of malaria infection.