The DNA content of osteosarcomas, and of giant cell tumors, osteoblastomas, aneurysmal bone cysts, and fibrous dysplasias was determined by cytophotometry. Out of 158 tumors, 141 were histologically noncontroversial, whereas 17 posed diagnostic difficulties. In the noncontroversial group all 41 benign tumors had a diploid (normal) DNA content. Ninety-two of 96 high-grade osteosarcomas were hyperploid (increased DNA content). The four analyzed low-grade parosteal osteosarcomas were diploid. Among 17 diagnostically controversial cases, nine were primarily diagnosed and treated as benign. Three of these patients, nevertheless, exhibited a malignant clinical course and two had local recurrence. All five proved to have hyperploid tumors. The four nonrecurrent lesions were diploid. Of eight cases primarily evaluated as malignant, one died and two developed local recurrence. These three patients had hyperploid tumors. Among the five nonrecurrent lesions, two were hyperploid and three diploid. Hence, in the diagnostically controversial group, recurrence or death was consistently related to hyperploidy. The current study shows that the vast majority of high-grade osteosarcomas are hyperploid. Benign bone tumors, which may be mixed up histologically with osteosarcoma, are diploid. Routine DNA analysis of primary bone tumors, as an adjunct to histopathologic assessment, can be employed to obtain diagnostic confirmation. In cases presenting histopathologic difficulties, ploidy determination may provide decisive diagnostic information.