The LPS defective (Lps(d)/Lps(d)) C3H/HeJ mouse, which is resistant to lipid A-induced effects, responds to orally administered erythrocytes as manifested by elevated splenic IgA immune responses when compared with lipid A-responsive C3H/HeN mice. This study demonstrates that the high splenic IgA immune responses obtained in C3H/HeJ mice is influenced by the Lps(d) gene, since F1 mice derived from mating LPS-responsive C3H/HeN and nonresponsive C3H/HeJ parents elicited intermediate splenic IgA immune and LPS mitogenic responses. Analysis of F2 offspring from crosses between (C3H/HeJ x C3H/HeN)F1 mice demonstrated co-inheritance of both IgA immune responsiveness and LPS sensitivity, which followed true Mendelian genetics, i.e., one-fourth of the offspring were high IgA and low LPS responders, one-fourth were low IgA and high LPS responders, and one-half were intermediate in both responses. These results demonstrated that the high splenic IgA immune response obtained in C3H/HeJ mice is influenced by the Lps(d) gene. Backcross analysis of offspring from (C3H/HeN)F1 matings with either C3H/HeN (LPS-responsive) or C3H/HeJ parents further demonstrated that the ability of mice to elicit elevated splenic IgA immune responses to orally administered antigen was due to the expression of the Lps(d) gene. This response pattern was not unique for the C3H/HeJ mouse, since the C57BL/10ScN mouse, which is also defective in LPS responsiveness, elicited high splenic IgA immune responses to orally administered antigen. F1 mice derived from crosses between C57BL/10ScN and C57BL/10Sn (LPS responsive) parents yielded intermediate splenic IgA immune responses. These results suggest that elevated IgA responses in C3H/HeJ mice result from lack of LPS influence on T and B cells in gut-associated lymphoid tissue, which is of central importance in the induction of IgA responses.