Intranasal immunization results in both a mucosal and a systemic immune response in humans. Intranasal tetanus toxoid immunization in humans causes an increased serum IgA1 antibody response to tetanus toxoid following a subsequent intramuscular immunization. We hypothesized that intranasal priming with a novel protein antigen, keyhole limpet hemocyanin (KLH), would similarly result in an upregulated systemic IgA response after a subsequent systemic immunization. To test this hypothesis, five healthy adults received a primary series of intranasal KLH immunizations followed 3 months later by a subcutaneous KLH immunization. Eight healthy adults received only a subcutaneous KLH immunization and served as controls. The nasal immunization resulted in a brisk and sustained serum IgM, IgA, and IgG antibody response and a mucosal IgA response. The subcutaneous immunization alone resulted in a serum antibody response and the development of delayed type hypersensitivity by skin testing. When the nasally primed subjects received a subsequent subcutaneous immunization there was a decline in the serum concentration of IgA and IgG antibodies to KLH. In addition, the nasally primed subjects failed to develop delayed type hypersensitivity to KLH following subcutaneous immunization. These data suggest that the nasal mucosa can induce a mucosal and systemic response; however, it may also suppress a subsequent immune response to systemic immunization. © 1994 Academic Press. All rights reserved.