Because our past studies hav shown that oral administration of thymic-dependent antigens induces higher IgA responses in lipopolysaccharide (LPS) nonresponsive C3H/HeJ mice than in syngeneic, LPS-responsive C3H/HeN animals, it was of interest to compare anti-LPS responses in these mouse strains after oral administration of particulate antigens containing LPS. C3H/HeJ and C3H/HeN mice were given smooth Salmonella typhimurium LT-2 or rough S. minnesota Rb (R345) or Re (R595) organisms by gastric intubation for 3 consecutive days/wk for 2 wk and were boosted by the i.v. route with either the same bacterial immunogen or with purified homologous LPS. Four days later splenic anti-LPS plaque-forming cell (PFC) responses were assessed with a panel of indicator sheep erythrocytes (SRBC) coated with LPS derived from either smooth (S-LPS-SRBC) or rough (Rb-LPS-SRBC or Re-LPS-SRBC) Salmonella. In separate studies, both serum and salivary antibodies of the IgM, IgG, and IgA isotypes were determined by ELISA, with whole Salmonella cells used as the coating antigen. Oral immunization with LT-2 resulted in good IgM, IgG1 and IgA splenic anti-LPS PFC responses in C3H/HeJ mice with the major isotype being IgA. Mice boosted i.v. with purified LPS gave five- to sixfold higher anti-S-LPS PFC responses than did mice given whole bacteria by the i.v. route. Low anti-Rb-LPS and anti-Re-LPS PFC responses were seen in both mouse strains. Enhanced immune responses in orally primed C3H/HeJ mice was not due to LPS-induced polyclonal responses, because splenic cultures from these mice gave poor mitogenic responses to LPS. A similar pattern of response was obtained when C3H/HeJ or C3H/HeN mice were given Rb (R345) or Re (R595) bacteria orally and boosted i.v. with purified homologous LPS or whole cells. C3H/HeJ mice again showed higher immune responses in all isotypes than did C3H/HeN animals. Mice given Rb (R345) immunogen gave maximum responses to Rb-LPS, lower responses to Re-LPS, and no responses to S-LPS, whereas C3H/HeJ mice immunized with Re (R595) immunogen gave maximum PFC responses to Re-LPS and lower responses to Rb-LPS. Serum and salivary antibody titers closely paralleled the specific PFC responses, and IgA antibodies were the predominant isotype observed, with higher IgA responses occurring in orally immunized C3H/HeJ mice than in C3H/HeN animals. These results clearly indicate that C3H/HeJ mice given whole Salmonella by gastric intubation elicit higher PFC and antibody responses to the three major LPS regions than do identically treated LPS-responsive C3H/HeN mice.