We have previously demonstrated that a wide variety of rodent and human tumor cells secrete markedly elevated levels of a transformation-related phosphoprotein with a molecular weight (depending on animal species) of 58,000 to 69,000. With antibody raised to the tumor-secreted phosphoprotein (rat), we have now identified an antigenically related protein in normal rat and human plasma. The rat plasma protein and the rat tumor-secreted phosphoproteins comigrated on polyacrylamide gels and were identically cleaved during blood coagulation as well as by purified thrombin. Mouse macrophages expressed a similar or identical phosphoprotein suggesting that monocytic cells may be a source of the normal plasma protein. Consistent with elevated secretion of this protein by tumor cells, plasma and sera from cancer patients contained elevated levels of this protein, raising the possibility that this circulating marker may prove useful for monitoring tumor burden. Amino acid sequence derived from the amino terminus of the rat tumor phosphoprotein indicates that it is distinct from previously sequenced proteins, but that it may be related to protein-tyrosine kinases encoded by viral and proto-onc genes.