Fine structural studies of leukocytes from four patients with the Chediak-Higashi syndrome, including two in the accelerated phase, demonstrate a pleomorphism of substructure of the giant lysosome-like organelles pathognomonic of this syndrome. These organelles differ in composition in relationship to the cell type in which they occur. Many circulating lymphoid cells have altered nuclear chromatin and a diminution in cytoplasmic constituents. Virus-like particles are not seen and there is no evidence of abnormal cytoplasmic sequestration. Large abnormal lysosome-like organelles are present in a small percentage of lymphoid cells from the six parents of these patients, demonstrating that heterozygotes exhibit a cellular abnormality in vivo.