We studied the effects of preload on transmural myocardial perfusion and coronary pressure-flow relationships in mongrel dogs. The left circumflex (LC) artery was cannulated and perfused through an external circuit of rigid tubing originating in the left subclavian artery and containing an electromagnetic flowmeter (EMF), a solenoid, and a short segment of soft tubing which could be occluded. The solenoid, triggered by the R-wave of the ECG, was adjusted so that perfusion occurred only during diastole. Autoregulation was abolished by maximal vasodilation with carbocromen. In 16 dogs, overall radioactive microsphere flow in the perfused LC segment was 1.67 ± 0.17 (SKM) ml/min per g at normal preload and 1.54 ± 0.19 ml/min per g at elevated preload. The endocardial: epicardial flow ratio decreased from 0.76 ± 0.03 at normal preload to 0.55 ± 0.04 at elevated preload (P< 0.01). EMF pressure-flow curves, determined by stepwise constriction of the perfusion circuit in the same dogs, showed a rightward shift with increased preload and an increase in PZF, the pressure at which inflow became zero (12 ± 0.9 nun Hg at normal preload vs. 19 ± 1.0 mm Hg at elevated preload,P< 0.01). Microsphere pressure-flow curves in eight additional dogs suggested that a small endocardial: epicardial difference in diastolic PZF at normal preload is accentuated at elevated preload. We conclude that effects of increased preload produced by volume expansion are 2-fold: (1) a selective reduction of flow in the inner layers of the heart, and (2) a shift to the right of the diastolic pressure-flow relationship. The former seems reasonably related to direct effects of preload on intramyocardial tissue pressure, whereas the latter suggests additional effects of local reflex, myogenic or mechanical phenomena. Circ Res 46: 68-77, 1979