We evaluated the consequences of excess free fatty acids (FFA) on mechanical and metabolic functions in globally perfused working swine hearts. In one group of eight hearts, treatments with heparin and 10% fat emulsion (Intralipid) produced a 3- to 5-fold elevation in serum FFA levels as contrasted with levels in 10 untreated hearts. At control flows, excess FFA caused declines in aortic pressure (−31.4%, P < 0.05), left ventricular systolic pressure (−24.8, P < 0.05), left ventricular work (−69.8%, P < 0.001), and epicardial motion (−57.8%, P < 0.001), together with an increase in myocardial oxygen consumption (+16.5%, P < 0.05) as compared to pretreatment values. Ischemia in untreated hearts also decreased mean aortic pressure (−46.2%, P < 0.005), left ventricular systolic pressure (−19.5%, P < 0.001), left ventricular max dp/dt (−27.9%, P < 0.001), left ventricular work (−49.1%, P < 0.025), myocardial oxygen consumption (−21.2%, P < 0.001) as compared with preischemic values. Excess FFA during ischemia resulted in even greater deteriorations in hemodynamic and metabolic functions. Tissue metabolites in the two groups of ischemic hearts were compared with those in six untreated hearts maintained at control flows. Tissue levels (mfiM/g dry weight) of long-chain acyl coenzyme A (CoA) esters were 70.1 ± 6.5, 121.4 ± 11.1 (P < 0.001), and 174.7 ± 13.7 (P < 0.001) in control, ischemic with normal FFA, and ischemic with excess FFA hearts, respectively. Tissue fatty acyl carnitine levels (imiM/g dry) were 20.6 ± 9.8, 380.1 ± 51.6 (P< 0.001), and 685.1 ± 115.7 (P< 0.001) in control, ischemic with normal FFA, and ischemic with excess FFA hearts, respectively. Thus, excess FFA caused significant impairments in cardiac function in association with elevations in tissue acyl CoA and acyl carnitine derivatives during ischemia. Accumulations of these products of fatty acid metabolism may interfere with enzyme functions and membrane transport systems.