For six weeks, recipient (Lewis RT11) and donor rats (LBNF11/n) were fed three diets that varied only in their lipid content. Diet A (MO) contained 19.5% menhaden oil and 0.5% safflower oil and was rich in omega 3 PUFA; diet B (SO) was 20% safflower oil rich in omega 6 PUFA; and diet C (BT) was 20% beef tallow rich in omega 9 monounsaturated fatty acids and saturated fat. In the first set of graft survival studies a group fed laboratory chow was included (CHOW). Heterotopic cardiac transplantation from donor to recipient animals was performed after the six-week feeding period. The effect of these diets on cardiac allograft survival, mixed lymphocyte response, and blood flow in the rejecting grafts was investigated. The median graft survival in days was significantly prolonged in the rats maintained on either MO (12 days) or SO (14.5 days) compared with the BT (8 days)-or lab chow (7.5 days)-fed animals (P < 0.05). Cyclosporine (CsA) administered at subtherapeutic levels further increased the differences between the PUFA-fed animals and the BT-fed group. The myocardial blood flow of the rejecting allografts was measured using an 85Sr-labeled microsphere technique on the fifth posttransplant day. Flow was greatest in the MO-fed group, and both MO and SO groups had significantly higher myocardial blood flow than BT-fed rats (P < 0.05) or those bearing isografts. The allogenic mixed lymphocyte responses of peripheral blood mononuclear cells (PBMC) and splenic lymphocytes were suppressed in MO- and SO-fed groups compared with BT-fed animals. The immunosuppressive effect of dietary PUFA warrants further investigation, and their use as a possible adjunctive treatment in organ transplantation should be considered.