Clear-cell carcinoma is a convenient and frequently used descriptive term for a malignant epithelial neoplasm that is entirely or largely composed of cells with optically clear cytoplasm in hematoxylin-eosin-stained sections. Transmission electron microscopy was performed on 57 tumors from various sites to investigate the fine structural basis for the clarity of the cytoplasm. The clear appearance resulted from the presence of one or several of the following features, as the sole or predominant cause or in combination: glycogen, lipid droplets, mucin vacuoles or diffuse mucosubstances, dilated cisternae, swollen or unusually large mitochondria, large solitary membrane-limited vacuoles or numerous smaller vacuoles, intracytoplasmic lumens, expanded intercellular spaces, cytoplasmic pseudoinclusions, and a paucity of organelles. Degenerative changes contributed to the clear appearance by inducing swelling of mitochondria and creating lucent cytosol. The factors responsible for the clear cytoplasm were not always consistent with regard to tumor type or site of origin, but glycogen was the commonest reason among the 57 tumors studied and the principal cause in tumors of the female genital tract, skin, and salivary glands, while renal cell carcinomas tended to possess an admixture of glycogen and lipid droplets. Because of the heterogeneity of the subcellular changes that can produce optically clear cytoplasm, electron microscopy has a limited role in determining the primary site of a metastatic clear-cell carcinoma.