Protective effects of essential fatty acid deficiency (EFAD) on autoimmunity were shown in rodents. Our goal was to investigate the mechanisms of EFAD effects on autoimmune diabetes in nonobese diabetic (NOD) mice. Weanling female mice were randomized between a control diet group and an EFAD diet group, and the development of diabetes and immune response was determined over a 6-month period. The cumulative incidence of diabetes was significantly reduced in the EFAD group (20 vs 68.75% in the control group; p < 0.01), without affecting the insulitis process. Splenocyte reactivity to phytohemagglutinin and anti-CD3 antibody was significantly increased in EFAD-fed mice (p < 0.01). The EFAD group also exhibited a dramatic increase in baseline (29-fold) and antigen-presenting cell (APC)-stimulated (10-fold) T cell responses in syngeneic mixed leukocyte reaction. These responses were associated with a marked increase in splenocyte interleukin-4 (IL-4) production, a reduction in interferon-gamma production, and a down-regulation of CD45RB isoform expression. Macrophages in the EFAD group exerted a reduced suppressive effect on concanavalin A-induced splenocyte proliferation and were found to release increased amounts of tumor necrosis factor-alpha and IL-1 and reduced amounts of prostaglandin E2. These results clearly demonstrate that EFAD prevents diabetes in NOD mice. The data suggest an enhanced activity of Th2-like cells, as well as an effect on APC activity linked to alteration in eicosanoid metabolism.