Chronic energy intake restriction (CEIR) prolonged the median life span and inhibited autoimmunity and development of autoimmune disease in BXSB mice, as has been established for mice of several other autoimmune-prone, short-lived strains. Whether imposed just after weaning or delayed until manifestations of disease had appeared, CEIR inhibited or reversed development of autoimmunity and immune complex-based renal disease in male BXSB mice. CEIR also prevented the formation of anti-DNA antibodies and prevented the increase in circulating immune complex levels that is typically observed in male mice of this strain. Moreover, CEIR inhibited development of splenomegaly and prevented the normal age-associated decline of a number of immunological functions, including interleukin 2 production, cellmediated cytotoxic responses, and mixed lymphocyte reactivity. The observed improvement in cell-mediated immune responses was attributed largely to the capacity of CEIR to inhibit development of the splenomegaly that occurs concomitant with expansion of a non-T, non-B lymphoid cell population. These findings emphasize that CEIR, even when imposed relatively late in life in BXSB mice, can influence expression of autoimmunities and autoimmune diseases of different genetic origins and presumed pathogenetic bases.