Five patients on continuous ambulatory peritoneal dialysis (CAPD) were immunized intraperitoneally with tetanus toxoid (TT) through an indwelling catheter. Four control patients on CAPD received the same dose of TT intramuscularly. Before immunization, virtually no anti-TT antibody-secreting cells (AbSC) were detected by the enzyme-linked immunospot (ELISPOT) assay in peripheral blood or peritoneal fluid from patients of either group. One to 2 weeks after immunization, high frequencies of TT-specific AbSC were detected in the circulation and peritoneal cavity. More than 80% of those cells were of the IgG isotype, with IgA accounting for most of the remainder. Patients receiving TT by the i.p. route showed significantly higher frequencies of specific IgG and IgA AbSC in the peritoneal cavity than patients immunized intramuscularly. Frequencies of AbSC in peripheral blood did not significantly differ between the two groups. Immunization with TT by both routes resulted in a significant increase of IgG anti-TT antibodies in serum, saliva and peritoneal fluid. A significant IgA antibody response was seen only in serum and peritoneal effluents. Therefore, i.p. immunization of human subjects with TT elicited both a localized response in the peritoneal cavity as well as a systemic response in serum, but did not induce a salivary IgA response.