Primary cytotoxic T lymphocyte (CTL) and helper T (Th) cell responses were generated from regional lymph nodes of heterozygous mice sensitized in the footpad with spleen cells of parental H-2 genotype but differing for multiple minor alloantigens of the B10 background. Cytotoxic and helper responses were read after a short in vitro culture period, which did not influence the restriction specificities of in vivo sensitized T cells. We show that under these conditions, Th cell responses appear unrestricted, whereas CTL responses are restricted to the immunizing parental H-2 genotype. Furthermore, we present evidence that these two functions are mediated by distinct T cell subsets and that the in vivo induction of Lyt-2- Th cells has the appearance of being unrestricted whereas that of Lyt-2+ CTL is restricted by H-2. These findings suggest that in a primary immune response, in vivo precursors of Th cells recognize processed antigen on F1 antigen-presenting cells (clones restricted to each parental H-2 genotype are cross-sensitized) under conditions in which those of CTL only respond directly to foreign minor alloantigens on the injected stimulator cells (clones restricted to parental H-2 genotypes are not cross-immunized). This dichotomy is taken to suggest the possibility that processing of cell membrane-bound antigens is controlled at their association step with products of the major histocompatibility complex.