Inbred congenic mice of strains MRL/Mp-lpr/lpr (lpr/lpr) and MRL/Mp(-)+/+ (+/+) were fed nutritionally adequate semipurified diets containing 20% (w/w) fat and differing in linoleic acid content. Levels of linoleic acid (18:2n-6) and arachidonic acid (20:4n-6) in phospholipids of splenocytes, liver mitochondria and liver nuclear envelopes were determined. Membranes of lpr/lpr mice exhibited significantly lower levels of 18:2n-6 and 20:4n-6 in phospholipids compared with the +/+ strain. The high linoleic acid diet increased incorporation of 18:2n-6 and 20:4n-6 in most phospholipid fractions of these membranes. These observations indicate that genotype as well as dietary 18:2n-6 content significantly influenced incorporation of 18:2n-6 and 20:4n-6 into membrane phospholipids. The results also suggest that membrane compositional abnormalities found in the lpr/lpr mice, which develop lymphoma and age faster than +/+ mice, are not restricted to the immune system but also extend to other organs. Differences observed in phospholipid fatty acid composition in splenocytes and liver subcellular membranes for mice fed diets differing in linoleic acid content suggest that the early expression of the lpr gene resulting in progression of autoimmunity may be delayed through dietary manipulation.