Soluble forms of the two molecular species of the cell surface receptors for tumor necrosis factor (TNF) have been detected in normal urine. Using enzyme-linked immunosorbent assays for these soluble receptors, we determined their levels in the sera of 40 healthy subjects and 59 patients with solid tumors. The mean +/- SD concentrations of both the soluble type I (p55) and type II (p75) receptors were significantly higher in the cancer patients than in the healthy controls: 1.96 +/- 1.19 versus 0.79 +/- 0.19 ng/ml (P less than 0.001) and 6.43 +/- 4.8 versus 3.2 +/- 0.6 ng/ml (P less than 0.001), respectively. The incidence and the extent of the increase correlated with the staging of disease. Sera of the cancer patients had a marked inhibitory effect on the in vitro cytocidal activity of TNF. This inhibition was proportional to the content of soluble TNF receptors and could be fully abolished by the addition to the sera of specific antibodies against the receptors. Among the cancer patients, the incidence of increase in the concentrations of soluble TNF receptors (about 70%) greatly exceeded that of the serum carcinoembryonic antigen (about 26%), a commonly used cancer marker. The origin of the serum soluble TNF receptors in cancer patients and the physiological implications of their effect on TNF function remain to be elucidated.