Cancer is commonly associated with the inappropriate mRNA expression of nonmutated genes. Recently, several tumor-associated RNA species, including tyrosinase mRNA and telomerase RNA, have been demonstrated in plasma and serum. The presence of tumor RNA in plasma and serum affords the opportunity to diagnose or stratify patients with cancer when tissue is not readily available. To exemplify the potential for pharmacogenomic and phenotypic stratification of the cancer patient, we evaluated serum for 5T4 mRNA. 5T4 is a trophoblast glycoprotein frequently overexpressed in epithelial malignancies that provides a potential target for cancer therapeutics. Serum was collected from 19 patients with advanced breast cancer (5 patients) or non-small-cell lung cancer (14 patients), and from 25 normal control volunteers having amplifiable RNA. RNA extracted from the serum was RT-PCR amplified using heminested, two-stage reactions, with products detected by gel electrophoresis. 5T4 mRNA was reproducibly detected in 8/19 (42%) cancer patient sera, including 2/5 breast cancer patient sera and 6/14 lung cancer patient sera, but in only 3/25 (12%) normal control sera (p = 0.035). The potential for circulating mRNA to identify patients who might benefit from a 5T4-directed therapy offers an example of the utility of circulating RNA as a tumor marker.