It has been shown that dietary red palm oil (RPO) supplementation improved reperfusion function. However, no exact protective cellular mechanisms have been established. Our aim was to search for a possible cellular mechanism and a role for fatty acids. Rats were fed a standard rat chow, plus cholesterol and/or RPO-supplementation for 6 weeks. Functional recovery, myocardial phospholipid and cAMP/cGMP levels were determined in isolated rat hearts subjected to 25 min of normothermic total global ischaemia. Dietary RPO in the presence of cholesterol improved aortic output (AO) recovery (63.2ᳮ06%, P<0.05) vs. cholesterol only (36.5ᶮ2%). The improved functional recovery in hearts supplemented with RPO vs. control was preceded by an elevation in the cGMP levels early in ischaemia (RPO 132.9ᳶ.3% vs. control 42.7Ჴ.4%, P<0.05). Concurrently, cAMP levels decreased (RPO -8.3ᶮ9% vs. control 19.9ᷮ7%, P<0.05). Our data suggest that dietary RPO-supplementation improved reperfusion AO through mechanisms that may include activation of the NO-cGMP and inhibition of the cAMP pathway.