Measurement of myocardial and brain perfusion when using exogenous contrast agents (CAs) such as gadolinium-DTPA (Gd-DTPA) and MRI is affected by the diffusion of water between compartments. This water exchange may have an impact on signal enhancement, or, equivalently, on the longitudinal relaxation rate, and could therefore cause a systematic error in the calculation of perfusion (F) or the perfusionrelated parameter, the unidirectional influx constant over the capillary membranes (K i ). The aim of this study was to quantify the effect of water exchange on estimated perfusion (F or K i ) by using a realistic simulation. These results were verified by in vivo studies of the heart and brain in humans. The conclusion is that water exchange between the vascular and extravascular extracellular space has no effect on K i estimation in the myocardium when a normal dose of Gd-DTPA is used. Water exchange can have a significant effect on perfusion estimation (F) in the brain when using Gd-DTPA, where it acts as an intravascular contrast agent. Measurement of perfusion when using exogenous contrast agents (CAs) and MRI is affected by the diffusion of water between compartments. Several studies have indicated that this could affect the results of such perfusion measurements (1-6). However, contrast-enhanced MRI using T 1 -weighted imaging has been developed in order to measure perfusion or perfusion-related parameters of the heart in vivo without explicitly considering the effect of water exchange. Models of perfusion in animals and humans when using extravascular CAs such as gadolinium-DTPA (Gd-DTPA) or intravascular CA have been presented (7-12). These measurements are often based on inversion recovery turboFLASH (IR-turboFLASH) or saturation recovery turboFLASH (SAT-turboFLASH) imaging.Most of these studies measure the tissue enhancement curve and the arterial input function and rely on basic tracer kinetic models as formulated by Kety (13). In the ideal case, this approach gives the unidirectional influx constant K i (ml/100 g/min) for CA diffusion over the capillary membrane when extravascular CA is used and the perfusion F (ml/100 g/min) when intravascular CA is used. For extravascular CA, the perfusion and the unidirectional influx constant are related by K i ϭ EF (14), where E is the unidirectional extraction fraction in the first pass.There is now growing evidence that K i in particular provides valuable and clinically useful information related to perfusion (7-12,15). For example, it has been shown previously that infusion of dipyridamole in humans resulted in an increase of K i by a factor of 2-3 in the heart of healthy subjects. In patients with ischemic heart disease, K i was either unaffected or decreased after infusion of dipyridamole in areas supplied by an insufficient coronary artery (16,17).Many assumptions need to be investigated in order to clearly associate directly the MRI-determined K i with the physiological parameter, the unidirectional influx constant of the CA diffusion over the capillary mem...