The purpose of the present studies was to contrast the differences in mechanical and metabolic functions between treatments of L- and D-carnitine as measured in intact, regionally ischemic swine hearts. Coronary flows were decreased in the anterior descending circulation (-53% delta) after an equilibration period of 30 min during which hearts in both treatment groups were supplemented with trace-labeled [U14-C]palmitate. Nine hearts were selectively treated with L-carnitine (avg serum concentration 804 nmol/ml) and were compared with eight hearts treated with D-carnitine (same dosage schedule). No differences in fatty acid metabolism or regional shortening were observed between treatment groups in the heart muscle rendered moderate-to-severely ischemic. L-Carnitine did effect a significant reduction in fatty acid uptake and labeled CO2 production as compared with D-carnitine in aerobic tissue. This resulted in a secondary improvement in global mechanical efficiency (expressed as a ratio of either left ventricular developed pressure or work/global oxygen consumption) in L-treated hearts. Higher levels of high-energy phosphate stores were also noted in both ischemic and aerobic tissue of L-treated hearts. Thus differences in fatty acid metabolism occurred in working swine hearts based on the structural specificity of carnitine treatment. L-Carnitine favorably modified oxygen consumption and global mechanical efficiency.