Near-isocaloric diets with qualitative and quantitative differences in fat content have a profound influence on the manifestation and progression of the autoimmune syndrome that occurs in female MRL/lpr mice. In these animals, a high (9%) lipid intake resulted in a significantly higher mortality rate: 60% (saturated fat) and 75% (unsaturated fat) compared to 35% at 1 year for a group fed a diet low in fat. Furthermore, beginning at 7 months of age mice from both of the high fat diet groups exhibited a significantly higher incidence of proteinuria than mice in the low fat group. Immunologically, the group fed the high unsaturated fat diet had the highest incidence of anti-dsDNA autoantibodies, and the high saturated fat group had the poorest macrophage phagocytic function. The low fat diet preserved near 'normal' immune function in general, particularly IL-2 production. No significant differences were noted in either the production of rheumatoid factor or natural killer cell activity, irrespective of age or diet.