Tumor vessel leakiness is attributed to defective endothelial monolayers with intercellular openings and transcellular holes. In MCa-IV mouse mammary carcinomas, 14% of vessel surfaces were lined by poorly connected, branched endothelial cells with cytoplasmic projections up to 50 µm. These cells formed irregular layers with intercellular openings (mean diameter 1.7 µm) and transcellular holes (mean diameter 0.6 µm). These openings and holes contribute to vessel leakiness, allowing macromolecular drugs to reach tumor cells. Tumor vessels in RIP-Tag2 mice also contained blood lakes of extravasated erythrocytes, which were not connected to the bloodstream. Scanning and transmission electron microscopy confirmed the presence of abnormal endothelial cells with irregular shapes, branched structures, and intercellular gaps. These abnormalities suggest that tumor vessels have a defective endothelial lining, which may explain their leakiness and facilitate drug delivery. The study highlights the structural basis of tumor vessel leakiness and its implications for cancer therapy.Tumor vessel leakiness is attributed to defective endothelial monolayers with intercellular openings and transcellular holes. In MCa-IV mouse mammary carcinomas, 14% of vessel surfaces were lined by poorly connected, branched endothelial cells with cytoplasmic projections up to 50 µm. These cells formed irregular layers with intercellular openings (mean diameter 1.7 µm) and transcellular holes (mean diameter 0.6 µm). These openings and holes contribute to vessel leakiness, allowing macromolecular drugs to reach tumor cells. Tumor vessels in RIP-Tag2 mice also contained blood lakes of extravasated erythrocytes, which were not connected to the bloodstream. Scanning and transmission electron microscopy confirmed the presence of abnormal endothelial cells with irregular shapes, branched structures, and intercellular gaps. These abnormalities suggest that tumor vessels have a defective endothelial lining, which may explain their leakiness and facilitate drug delivery. The study highlights the structural basis of tumor vessel leakiness and its implications for cancer therapy.