Antiphospholipid antibodies (aPL), prevalent in sera of patients with systemic lupus erythematosus (SLE), have been linked to thrombosis, thrombocytopenia, recurrent miscarriages, neurological disorders and ischemic heart disease. Most evidence suggests that phosphodiester-linked phosphate groups are the reactive epitope of cardiolipin (CL) in binding to aPL. Little attention has been given to the acyl moiety. To address this problem we have evaluated the ELISA binding of 12 highly positive IgG anticardiolipin antibody-positive SLE sera to: bovine CL (86.1% 18:2n-6), monolyso CL (MLCL; bovine CL minus 1 fatty acid), dilyso CL (DLCL; minus 2 fatty acids), tetraoleoyl CL (TOCL), myristoyl CL (MCL) and E. coli CL. The reductions in binding of the IgG aPL antibodies relative to bovine CL were as follows: DLCL 83%; MLCL 70.7%; MCL 58%; and TOCL 14% (P less than 0.05). These data suggest that the number of acyl chains and the unsaturation of the acyl chain of CL may be important determinants in the binding to aPL present in SLE sera. To investigate the nutritional relevance of this finding, we examined the incorporation of several dietary fatty acid classes into the CL pool of mice. Mice were fed diets containing n-6 (safflower oil), n-9 (olive oil) or n-3 fatty acids as either 18:3n-3 (linseed oil) or 20:5n-3/22:6n-3 (fish oil) for a 5 month period. The feeding of fish oil and olive oil resulted in replacement of a substantial portion of 18:2n-6 with 22:6n-3 or 18:1n-9, respectively. These results suggest that there may be therapeutic value in modifying the CL acyl composition by nutritional means with respect to binding to pathogenic aPL.