Organized epithelioid cell granulomas were produced experimentally by injecting intradermally dilute suspensions of zirconium and beryllium salts into individuals who had been previously sensitized to these metals. Biopsies were obtained at intervals of between 5 days and 13 months later, and the specimens were fixed and prepared for light and electron microscopy. Tritiated thymidine was injected into a number of the granulomas; the biopsy specimens were secured from 40 minutes to 2 or more weeks later, and the tissues were processed for light microscopic autoradiography. Giant cells occurred commonly, both within organized tubercles and in relation to areas of necrosis, and had markedly different cytoplasmic features from typical secretory epithelioid cells which enabled them to be readily recognized at scanning magnifications. The characteristic hallmark of these giant cells was the presence of myriads of small mitochondria adjacent to nuclei with numerous membrane-lined vesicles in the center of the cell. Giant cells occurred mainly in edematous disrupted tubercles. In these tubercles, epithelioid cells contained cytoplasmic components more like giant cells. Direct evidence of cell fusion was not seen, although fusion of membranes seemed to occur between cells having similar cytoplasmic features. The failure to find labeled nuclei in any giant cells 40 minutes after injection of tritiated thymidine indicates that normal nuclear division does not occur within giant cells. We postulate that epithelioid cells containing vesicles develop in damaged and necrotic areas, and that mainly this type of epithelioid cell fuses to form giant cells.