Twelve patients with primary and metastatic brain tumors were evaluated with [68Ga]ethylenediaminetetraacetate (EDTA) and positron computed tomography. Using a two-compartment tracer kinetic model, forward (K1) and reverse (k2) rate constants for molecular diffusion across the blood-brain barrier (BBB) were obtained and averaged 0.0029 +/- 0.0016 (mean +/- SD) ml/min/g for K1 and 0.0310 +/- 0.0156 min-1 for k2. Most tracer kinetic models are based on the assumption that tissue radioactivity contains no vascular component or require independent measures of cerebral blood volume (CBV) which are then subtracted from the measure tissue activity. The model in this work differs from that approach by assuming a vascular compartment in the tissue kinetic data. This vascular parameter is estimated from sequential measurements of activity concentrations in regions with an intact BBB or from measurements of 68Ga concentrations in the plasma (the input function). Thus, this approach does not require the assumption of a zero vascular contribution, does not require a separate measurement of CBV, and uses the criteria of constrained estimation to provide estimates of the local CBV and molecular diffusion through the BBB. Estimates of the relative CBV of the lesions in four studies (three subjects) with [68Ga]EDTA correlated well with those obtained with the C15O hemoglobin technique (correlation coefficient of 0.97).