Mono- and biexponential fitting of myocardial 11C-acetate kinetics does not account for the effect of recirculating 11C activity following intravenous injection of the tracer. A tracer kinetic model comprising two and three compartments was developed to describe intravascular and myocardial 11C-acetate kinetics defined by PET. This model approach including a correction for 11C-metabolites in blood was validated by correlating the model parameter estimates with directly measured oxygen consumption (MVO2) in 11 closed-chest dog experiments over a wide range of cardiac work. The model parameter k2 closely correlated with oxygen consumption (r = 0.94). This approach was subsequently applied to human studies and k2-related to rate-pressure product (PRP). In comparison to conventional monoexponential fitting of 11C-acetate tissue kinetics, the model approach improved the correlation coefficients of scintigraphic MVO2 estimates and PRP values from 0.61 to 0.91. Thus, analysis of myocardial 11C-acetate and clearance kinetics with a tracer kinetic model corrects for recirculating 11C-activity and may provide more consistent estimates of myocardial oxygen consumption.