Thirty-eight primary thyroid neoplasms with extensive (greater than or equal to 50%) clear cell changes were studied. These were divided into four categories: 1) Hürthle cell tumors, 10 cases; 2) follicular tumors, 17 cases (two of them having a signet-ring or lipoblast-like appearance); 3) papillary carcinomas, seven cases; and 4) undifferentiated carcinomas, four cases. These were compared with eight cases of renal cell carcinoma metastatic to the thyroid. Factors resulting in the cytoplasmic clear cell changes were: 1) formation of medium-sized vesicles, many of apparent mitochondrial derivation; 2) accumulation of glycogen (with or without accompanying fat); and 3) deposition of intracellular thyroglobulin. Vesicle formation was the most common cause of clear cell change in Hürthle cell and follicular tumors; glycogen accumulation in papillary, undifferentiated, and metastatic tumors; and thyroglobulin deposition in the subgroup of follicular tumors with a signet-ring or lipoblast-like appearance. However, several exceptions were noted. The results of this study refute the commonly held belief that all thyroid tumors containing clear cells are malignant, and do not support the concept of "clear cell carcinoma" of the thyroid as a specific microscopic entity. We believe that the natural history of thyroid tumors containing clear cells is more dependent on their basic cytoarchitectural features than on the presence, amount, or type of clear cells, and we suggest for these tumors to be evaluated for carcinoma by using standard morphologic criteria for their respective types. The importance of thyroglobulin staining for the differential diagnosis with metastatic renal cell carcinoma is emphasized, but the pitfalls inherent to this technique are also pointed out.