Renal cell carcinoma (RCC) is the most common form of cancer affecting the kidney. There is currently no biochemical marker for this disease. We have shown that serum-immunoreactive prostate-specific antigen (PSA) levels, as measured by the two-site Ciba-Corning ACS:180 immunochemiluminometric assay, are elevated in women with RCC. Although the levels were low (0.13-0.89 microgram/l), serum PSA was clearly measurable prior to surgery in 13 of 17 women (76%) with RCC. Significantly, the PSA levels fell to undetectable after nephrectomy. Seventeen normal women also had undetectable (<0. 1 microgram/l) PSA levels. Two women, who had several serum PSA measurements performed postoperatively, showed a t(1/2) of 2-3 days equivalent to that observed for PSA in men following radical prostatectomy for prostate cancer. The 17 RCCs evaluated in this study consisted of 10 stage A, 4 stage B, and 3 stage C tumors. There was no relationship between tumor size, stage, or serum-immunoreactive PSA level, although the majority of these tumors are low grade. We have shown by reverse transcription-PCR, using PCR primers directed to the NH2 terminal coding region of the KLK3 (PSA) gene and the closely related KLK1 and KLK2 genes, that these genes are not expressed in these tumors. Our findings show, however, that elevated levels of a circulating PSA-like protein are present in women with RCC.