Tumor necrosis factor (TNF) has significant biologic effects. Inhibitors of TNF have been isolated from urine and blood. We studied pleural fluid from 22 patients with benign or malignant effusions. Pleural macrophages from these effusions were capable of releasing TNF, especially when stimulated with lipopolysaccharide. The cell-free supernatant from some of these pleural effusions contained an inhibitor of TNF. Fluid from 12 malignant effusions contained an inhibitor of 17% +/- 15.4% (mean +/- SD) of 500 U/ml of TNF activity, whereas the mean inhibition in 10 benign effusions was 2% +/- 5.6% (p less than 0.05). Only one of 10 benign effusions had more than 10% inhibitory activity. This inhibitor was found to be heat sensitive and unaffected by dialysis, and the molecular weight of at least one of the inhibitors was 60 to 80,000 daltons. Enzyme digestion studies were consistent with a protein portion being the major determinant of activity. We conclude that some malignant effusions contain an inhibitor of TNF activity.