Caffeine causes a considerable O₂ waste for positive inotropism in myocardium by complex pharmacological mechanisms. However, no quantitative study has yet characterized the mechanoenergetics of caffeine, particularly its O₂ cost of contractility in the E_max-PVA-VO₂ framework. Here, E_max is an index of ventricular contractility, PVA is a measure of total mechanical energy generated by ventricular contraction, and VO₂ is O₂ consumption of ventricular contraction. The E_max-PVA-VO₂ framework proved to be powerful in cardiac mechanoenergetics. We therefore studied the effects of intracoronary caffeine at concentrations lower than 1 mmol/l on left ventricular (LV) E_max and VO₂ for excitation-contraction (E-C) coupling in the excised cross-circulated canine heart. We enhanced LV E_max by intracoronary infusion of caffeine after β-blockade with propranolol and compared this effect with that of calcium. We obtained the relation between LV VO₂ and PVA with E_max as a parameter. We then calculated the VO₂ for the E-C coupling by subtracting VO₂ under KCl arrest from the PVA-independent (or zero-PVA) VO₂ and the O₂ cost of E_max as the slope of the E-C coupling VO₂-E_max relation. We found that this cost was 40% greater on average for caffeine than for calcium. This result, for the first time, characterized integratively cardiac mechanoenergetics of the O₂ wasting effect of the complex inotropic mechanisms of intracoronary caffeine at concentrations lower than 1 mmol/l in a beating whole heart.