The tumor microvasculature is hyperpermeable to plasma proteins, but the specific vessels that leak have not been identified. To investigate this question, the extravasation of circulating tracers of varying size was studied by fluorescence, light, and electron microscopy in animals bearing solid transplantable carcinomas. In all five tumors studied, 70 and 150 kD fluoresceinated (FITC)-dextrans and colloidal carbon leaked extensively from the prominent vascular plexus that was induced around individual tumor nodules and at the tumor-host interface. Leaky vessels were mature veins or venules, lined by a continuous endothelium; most had closed interendothelial cell junctions. Immature interface vessels and tumor-penetrating vessels did not leak these macromolecular tracers significantly. Three kD of FITC-dextran leaked from peripherally situated tumor veins or venules but also extravasated from tumor-penetrating vessels and capillaries supplying normal tissues. These data correlate the functional and anatomic heterogeneity of tumor vessels and provide a rationale for the distribution of circulating molecules such as monoclonal antibodies and tumoricidal drugs in solid tumors.