Omega-3 polyunsaturated fatty acids (omega 3-PUFAs) from fish oil modulate various ion channels, including the L-type calcium current (I(Ca,L)). As a result, fish oil shortens the cardiac action potential and may cause a loss of the dome of the action potential (AP). Under conditions of increased preexisting heterogeneity in repolarization this may aggravate dispersion in action potential duration. We isolated ventricular myocytes of explanted hearts from patients with cardiomyopathy at the time of cardiac transplantation, and characterized spike-and-dome morphology in the presence of acutely administered fish oil. Fish oil omega 3-PUFA eicosapentaenoic acid (EPA), but not the control omega 9-PUFA oleic acid (OA), curtails the AP-dome in a heterogeneous manner and may even result in loss of the AP-dome in some but not all myocytes.