The liver-specific F antigen, although not an autoimmunogen, can induce the production of autoantibodies in responder strains. The ability to respond is under the control of two genes, one linked to the H-2 locus of mice, the other not. Responders possessing both genes produce high anti-F titers, while the H-2-linked gene alone permits a significant but low antibody response. (Responder X nonresponder) F1 hybrids derived from parents possessing identical F molecules are nonresponders, in contrast with the dominance of responsiveness in Ir gene systems. The presence of the H-2 locus from nonresponders appears involved in the inability to respond. This is discussed in terms of self-tolerance and suppression.