An important role for the p53 gene in neoplastic transformation in vitro and in vivo has been imputed by functional studies and identification of tumor-acquired gene defects or alterations in its expression. To study the generality and mechanisms of p53 alteration in human cancer, we examined 241 tumors of several types for structural aberrations of the locus. Alterations of the gene or its RNA or protein products consistent with loss of function by either recessive or dominant mechanisms were identified among this set uniquely in rhabdomyosarcomas and osteosarcomas. The alterations of p53 in rhabdomyosarcoma tumors included cases with complete deletion of both p53 alleles, complete deletions of one allele with or without point mutation of the remaining allele, and absence of detectable RNA. Similarly, we detected homozygous deletion and lack of expression of p53 RNA or aberrant expression of p53 protein in osteosarcomas. These observations provide strong support for the inclusion of the p53 locus in the group of loci whose functional inactivation by either dominant or recessive modes plays a significant role in human cancer.