Adjuvant arthritis (AA) can be induced in Lewis rats by immunization with mycobacterial antigens. Passive transfer of a T cell clone recognizing the 180–188 amino acid sequence in mycobacterial heat shock protein 60 (hsp60) was found to induce AA. In the present study, we investigated whether tolerance was obtained for this AA-associated T cell epitope after intranasal or s.c. administration of a peptide containing this epitope. Two 15-mer peptides containing the mycobacterial hsp60 sequences 176–190 and 211–225 were used; 176–190 contained the T cell epitope 180–188, which was recognized by the arthritogenic T cell clone A2b and was the immunodominant hsp60 T cell epitope after induction of AA, and 211–225 contained a T cell epitope that was recognized both after induction of arthritis with whole Mycobacterium tuberculosis and after immunization with mycobacterial hsp60. In rats treated intranasally or subcutaneously with 176–190 and immunized with mycobacterial hsp60, proliferative responses to 176–190 were reduced. Proliferative responses to 211–225 and to whole mycobacterial hsp60 were not affected. AA was inhibited intranasally in the 176–190-treated rats but not in the 211–225-treated rats. Moreover, intranasal 176–190 led to similar arthritis-protective effects in a nonmicrobially induced experimental arthritis (avridine-induced arthritis). Therefore, tolerance for a disease-triggering, microbial cartilage-mimicking epitope may cause resistance to arthritis irrespective of the actual trigger leading to development of the disease.