H-2d mice are resistant to measles virus-induced encephalitis (MVE) and develop Ld-restricted CD8+ T cells which lyse target cells infected with measles virus or with a vaccinia virus recombinant expressing the nucleocapsid protein of measles virus (vvN). In contrast, H-2k mice are susceptible to MVE and generate CD8+ T cells which lyse target cells infected with vvN, but not those infected with MV. We were able to demonstrate that this difference is not due to a defect in the antigen processing machinery, but that Kk molecules require 100-fold more peptide to sensitize target cells for lysis by CTL. vvN replicates well in target cells and therefore enhances the level of epitope peptide available for CTL recognition. In contrast, MV infection is abortive in mouse cells and low levels of epitope peptide are produced. As Ld requires 100-fold less peptide than Kk to sensitize target cells for lysis, the low level of epitope peptide is enough to induce lysis by CD8+ T cells, whereas for recognition via Kk, increased synthesis of protein is required. We propose that the differences in peptide binding between the two H-2 molecules will have consequences for the kinetics of the generation of CD8+ T cells as well as the absolute numbers of CD8+ T cells generated.