We examined 43 sporadic bone and soft-tissue sarcomas for molecular genetic alterations affecting the retinoblastoma susceptibility gene Rb-1 (also known as RB1). The gene was altered in 6 of 14 sporadic osteosarcomas and in 5 of 29 other bone and soft-tissue sarcomas. Rb-1 messenger RNA (mRNA) transcripts were detected in normal tissues and benign lipomas, but they were absent or altered in each of the 19 sarcomas we examined. To examine the association of deletions in the Rb-1 gene with tumor grade, we correlated the DNA alterations in the Rb-1 gene with clinical data for 36 patients. The Rb-1 gene was altered in 40% of high-grade bone and soft-tissue tumors, but not in low-grade bone tumors and in only one low-grade, soft-tissue sarcoma. Overall, 10 of 25 high-grade sarcomas had detectable alterations of the Rb-1 gene compared with only 1 of 11 low-grade tumors.