The mechanisms by which the contracting myocardium exerts extravascular forces (intramyocardial pressure, IMP) on coronary blood vessels and by which it affects the coronary flow remain incompletely understood. Several myocardium-vessel interaction (MVI) mechanisms have been proposed, but none can account for all the major flow features. In the present study, we hypothesized that only a specific combination of MVI mechanisms can account for all observed coronary flow features. Three basic interaction mechanisms (time-varying elasticity, myocardial shortening-induced intracellular pressure, and ventricular cavity-induced extracellular pressure) and their combinations were analyzed based on physical principles (conservation of mass and force equilibrium) in a realistic data-based vascular network. Mechanical properties of both vessel wall and myocardium were coupled through stress analysis to simulate the response of vessels to internal blood pressure and external (myocardial) mechanical loading. Predictions of transmural dynamic vascular pressure, diameter, and flow velocity were determined under each MVI mechanism and compared with reported data. The results show that none of the three basic mechanisms alone can account for the measured data. Only the combined effect of the cavity-induced extracellular pressure and the shortening-induced intramyocyte pressure provides good agreement with the majority of measurements. These findings have important implications for elucidating the physical basis of IMP and for understanding coronary phasic flow and coronary artery and microcirculatory disease.