The pressure pulse contour analysis method uses a third-order lumped model to evaluate the elastic properties of the arterial system and their modifications with adaptive responses or disease. A fundamental assumption underlying this method is that the estimates of model parameters (two compliances, an inertance, and a peripheral resistance) obtained from a measurement of cardiac output, and a simultaneous measurement of an arterial pressure, are independent of the pressure measurement site. If true, this hypothesis would provide a minimally invasive method for estimation of arterial compliance. The aim of the present study was to test the validity of this assumption and the ability of the method to assess changes of compliance in response to vasoactive drug administration. In five anaesthetised, open-chest dogs we measured pulsatile pressure and flow in the ascending aorta and pulsatile pressure in the terminal aorta, under basal, vasoconstricted (methoxamine), and vasodilated (sodium nitroprusside) conditions. Model peripheral resistance was assumed equal to the ratio of mean pressure to cardiac output. Estimates of inertance and compliances, and the associated estimation errors, were determined by fitting the model output to either the diastolic portions of ascending aortic pressure, P(adt), or terminal aortic pressure, Ptd(t). Results showed that the assumption of independency of model parameter estimates on the arterial pressure measurement site was not verified. Different images of the vasoactive drug-induced changes in vascular compliance were obtained from fits to P(adt) and Ptd(t). Model parameter estimates were associated with high estimation errors and were very sensitive to the choice of the period of diastolic pressure to be fitted. Model predicted aortic pressure, over the entire heart cycle, did not compare well with experimental ascending aortic pressure. Our results question the reliability of the pressure pulse contour analysis method for evaluating arterial compliance.