The nuclear ultrastructure of sixteen human epithelial cell lines has been characterized in detail by transmission electron microscopy. The cell lines were derived from normal tissues, nonmalignant tissues of cancerous organs, primary carcinomas, and metastatic carcinomas. Every cell section on a grid containing a clearly defined nucleus and nucleolus was scored blindly utilizing a checklist of markers. The goal of these studies was to determine whether any ultrastructural markers consistently distinguished the different stages of malignant progression represented among the lines. Nuclear bodies and perichromatin granules were found in all lines derived from cancer and were not observed in any nonmalignant lines. Nuclear envelope dilation was seen in all lines derived from cancerours organs as well as from malignant tissues but not in any lines derived from normal tissue. Margination of chromatin, irregularity of nuclear outline, redistribution of nucleolar components, and margination were expressed slightly by the normal lines, to variable degrees by the lines derived from cancerous organs, and to a much greater extent by all lines derived from malignant tissues. No differences were found between lines derived from primary carcinomas and those derived from metastatic specimens. There were no ultrastructural differences comparing subconfluent and confluent cells or cells at different passage levels. In addition, the nuclear ultrastructure of a malignant line in culture was similar to that of a tumor induced by those cells in an immunosuppressed mouse.