The class-specific antibody response was measured in sequential serum samples from 17 patients after natural bacteremic infection with gram-negative bacilli. There was a five- to sevenfold mean increase over preexisting antibody in levels of IgG (range, less than 1-to 88-fold), IgA (1- to 83-fold), and IgM (less than 1- to 58-fold) antibody to homologous lipopolysaccharide (LPS) in 16 of these patients. In contrast, there was only a two- to threefold mean increase (range, less than 1- to 78-fold) in about half of the patients who had a detectable antibody response to J5 core determinants and in the third who responded to Re core determinants (range, 1- to 20-fold). All but one of the infective strains of bacteria were smooth on analysis with SDS-PAGE and with rough-specific phages. Humans infected with bacteria that had a rough LPS phenotype, however, did elicit antibody similar to that induced in rabbits after immunization with J5 vaccine. Thus, the human antibody response to natural infection with gram-negative bacilli appears to be directed primarily at homologous, strain-specific epitopes, and the response to the epitopes of LPS core antigens is not against widely shared determinants.