NOD mice spontaneously develop autoimmune diabetes that mimics insulin-dependent diabetes mellitus (IDDM) in man. A peptide of the 60 kDa heat shock protein (hsp60), designated p277, can serve as a target for diabetogenic T-cell clones, and diabetes was prevented by using the p277 peptide to turn off anti-p277 immunity early in life. We report that the p277 peptide, administered once, can arrest the autoimmune process even after it is far advanced. Successful therapy was associated with down-regulation of the autoimmune process and regression of islet inflammation. Thus the immune system is responsive to manipulation by a specific signal even in the face of a virulent, full-blown autoimmune process.