The shed portion of the 55 and 75 kDa membrane receptors for tumor necrosis factor (TNF) and lymphotoxin (LT) have been described in the serum of patients with cancer. This study was designed to determine whether serum levels of the 55 and 75 kDa soluble TNF/LT receptors (sTNFr) had clinical significance in patients with gynecologic malignancies. Serum samples from 79 patients with ovarian, endometrial, or cervical cancer were assayed for CA 125 levels by RIA and the 55 and 75 kDa sTNFr levels by ELISA. Receptor and CA 125 levels were also analyzed with respect to disease status and response to treatment in banked serum samples from 14 patients with epithelial ovarian cancer who had been followed clinically for 1-3 years. Patients resulted were compared to serum samples tested from normal donors. We found that serum levels of both sTNFr's were elevated in the 79 patients with various gynecologic malignancies [55 kDa of 3.07 +/- 3.79 ng/ml (P < 0.02) and 75 kDa of 2.93 +/- 1.27 ng/ml (P < 0.001)] compared to 16 normal controls (55 kDa of 0.65 +/- 0.22 ng/ml and 75 kDa of 1.62 +/- 0.37 ng/ml). Serum levels of 55 and 75 kDa TNF/LT receptors were a more sensitive indicator of active cancer and had greater predictive value for detecting tumor in patients with ovarian cancer than CA 125. The sTNFr's were also more sensitive than CA 125 in detecting persistent or recurrent tumor and measuring response to therapy. These preliminary results suggest that measurement of serum levels of 55 and 75 kDa sTNFr's, even though not tumor specific, may be a uniquely new method for identifying and monitoring patients with gynecologic malignancy.