The administration of soluble mouse thyroglobulin (MTg) in conjunction with bacterial lipopolysaccharide (LPS) led to the termination of natural tolerance to MTg in mice. The extent of autoimmunity correlated with responsiveness to MTg, previously shown by the injection of MTg in complete Freund's adjuvant (CFA) to be dependent upon the H-2 haplotype. In good responder B10.BR (H-2k) mice given MTg either with LPS or in CFA, high antibody levels to MTg and extensive mononuclear cell infiltration in the thyroid were observed. In contrast, congenic poor responder B10.D2 (H-2d) mice given MTg plus LPS showed low levels of antibody to MTg, compared to those receiving MTg in CFA, and insignificant cellular infiltration of the thyroid. In no instance did autoimmunity develop in either good or poor responder strain given MTg, LPS, or CFA along although LPS was antigenic in both of these congenic strains. Since the genetic difference in responsiveness to MTg is known to be T-cell based, the involvement of T cells in LPS-treated mice was suspected. This was further ascertained by the use of athymic poor responder (BALB/c) mice and thymectomized, irradiated, and bone marrow-reconstituted B10.BR mice. Antibodies to MTg were detected only in heterozygous (nu/+) mice and good responder mice reconstituted with both thymus and bone marrow cells. In addition, significant cellular infiltration in the thyroid occurred only in fully reconstituted good responder mice. Thus, the adjuvant effect of LPS on responsiveness to MTg required T cells. Since unmodified MTg and LPS abrogated selftolerance to MTg, the need for cross-reactive T cells could be excluded. These observations suggest the presence of self-reactive T cells.