The study of cytotoxic T cell (CTL) responses to measles polypeptides in persons with different HLA frequencies will provide information for the design of new vaccines. Peripheral blood mononuclear cells derived from African blacks and Caucasians were stimulated with measles virus-infected autologous cells and tested in a standard 51Cr-release assay against autologous B cells infected with vaccinia virus recombinants expressing measles virus antigens. The proportion of subjects who generated CTL to the fusion, hemagglutinin, and nucleoprotein antigens was 43%, 38%, and 28%, respectively. The use of HLA-mismatched targets showed killing to be restricted by both HLA class I and class II antigens, although CD8-mediated class I cytotoxicity predominated. Measles vaccine boosted CTL responses in subjects with low initial activity. These data suggest that the fusion and hemagglutinin proteins are important targets for the measles CTL response.