Daily gastric intubation of lipopolysaccharide (LPS)-responsive C3H/HeN, BALB/c, and Swiss mice with SRBC for 2 wk resulted in oral toerance, whereas similarly treated LPS-nonreponsive C3H/HeJ mice gave splenic anti-SRBC PFC responses, including the IgA isotype, after systemic challenge with antigen. Oral tolerance in LPS-responsive C3H/HeN mice was due to T suppressor (T(s)) cells because significant T(s) cell activity was demonstrated in both Peyer's patches (PP) and spleens of these animals. On the other hand, T cells from PP and spleens of identically treated C3H/HeJ mice exhibited mainly T helper cell activity. Prior treatment of PP or spleen cell preparations from tolerant C3H/HeN mice with antiLyt-2.1 resulted in good in vitro anti-SRBC PFC responses, especially IgA isotype responses in PP cell cultures. These results indicate that oral administration of thymic-dependent antigen (SRBC) to LPS-responsive mice induced a T(s) cell population in PP, which, after migration to peripheral lymphoid tissue (e.g., spleen), suppressed responses to systemically administered antigen. LPS-nonresponsive mice lack this T(s) cell pathway and continually respond to oral administration of antigen.