Six biopsies (4 of human fibrosarcomas, 1 of a B-cell lymphoma and 1 of a normal lymph node from a melanoma patient) and 6 cell lines (derived from 5 different human osteosarcomas and from 1 rhabdomyosarcoma), together with control cells, were examined for the expression of c-sis, c-fos and c-myc. The expression of c-sis/PDGF-B-related proteins was also examined in cultured cells (not in biopsies). In situ hybridization studies further showed that the occurrence and level of expression of c-sis mRNA and c-sis/PDGF-B-related proteins were significant in the tumor cells. Expression of c-fos and c-myc mRNA did not correlate with c-sis expression. Southern blot analysis of c-sis, c-fos and c-myc of 20 DNAs of cell lines derived from human sarcoma or biopsies showed an identical pattern for BamH1 and EcoR1 restriction fragments of c-sis (except for 1 fibrosarcoma biopsy), implicating no gene rearrangement as a cause of enhanced proto-oncogene expression. The nucleotide sequence of c-sis is highly homologous to that of the viral v-sis oncogene which is capable of transforming infected cells. We conclude that enhanced expression of c-sis in the sarcomas we have examined is involved in the initiation and/or maintenance of the cell transformed state.