Using a commercial kit with antibodies against the ectodomain of c-erbB-2 protein, we detected c-erbB-2 immunoreactivity in human serum. We found that the percentages of patients with elevated serum c-erbB-2 immunoreactivities were 35, 21, and 9% in breast, prostate, and ovarian carcinoma, respectively. The majority of the elevated immunoreactivities were associated with sera containing highly elevated tumor markers with the highest in breast carcinoma (35%) and lowest in ovarian cancer (9%). Excellent correlations were also observed between the serum levels of c-erbB-2 immunoreactivity and the dominant tumor markers in serial specimens from individual cancer patients. We could also detect the c-erbB-2 immunoreactivity in the cytosols prepared from the breast tumor tissue for estrogen and progesterone receptor (ER & PgR) measurements using the same commercial kit for serum studies, and the intact c-erbB-2 oncoprotein (p185) in the extracts of the tissue membrane fractions with a different kit designed for tissue extract. The level of c-erbB-2 immunoreactivity in the cytosol from 124 human breast tumor specimens had an excellent correlation with the cell membrane concentrations of p185 (gamma = 0.89). Most of the elevated cytosol c-erbB-2 immunoreactivities were also found to associate with breast tumor specimens containing low concentrations of ER & PgR. It appears that measuring the c-erbB-2 immunoreactivity potentially could be used as a prognostic marker without performing tissue biopsies and also as a serum tumor marker for managing cancer patients.