High-frequency QRS (HFQRS) analysis of surface ECG is a reliable marker of cardiac ischemia (CI). This study aimed to assess the response of HFQRS signals from standard intracardiac electrodes (iHFQRS) to CI in swine and compare them with conventional ST-segment deviations. Devices with three intracardiac leads were implanted in three swine in a controlled environment. CI was induced by inflating a balloon in epicardial coronary arteries. A designated signal-processing algorithm was applied to quantify the iHFQRS content before, during, and after each occlusion. iHFQRS time responses were compared to conventional ST-segment deviations. Thirty-three over thirty-nine (85%) of the occlusions presented significant reduction in the iHFQRS signal, preceding ST-segment change, being the only indicator of CI in brief occlusions. iHFQRS was found to be an early indicator for the onset of CI and demonstrated superior sensitivity to conventional ST-segment deviations during brief ischemic episodes.