The proinflammatory cytokines interleukin-1 and tumor necrosis factor-alpha are thought to play important roles in the pathophysiology of liver disease. Specific antagonists of these cytokines have been found in recent years. Interleukin-1 receptor antagonist is a specific interleukin-1 antagonist. The soluble receptor derived from the cell-surface p55 tumor necrosis factor receptor p55 is a naturally occurring substance that inhibits the biological effects of tumor necrosis factor. We used specific radioimmunoassays to detect circulating interleukin-1 receptor antagonist and tumor necrosis factor soluble receptor p55 levels in 14 patients with acute viral hepatitis and in 160 patients with various chronic liver diseases. Levels of interleukin-1 receptor antagonist and, especially, tumor necrosis factor soluble receptor were markedly increased in most patients with chronic liver disease regardless of pathogenesis and in viral hepatitis. Patients with chronic liver disease and cirrhosis showed significantly higher levels of both cytokine antagonists than did noncirrhotic patients. Correlations between interleukin-1 receptor antagonist and tumor necrosis factor soluble receptor were more significant than those of either antagonist with C-reactive protein or blood sedimentation rate. Interleukin-1 receptor antagonist and tumor necrosis factor soluble receptor levels were also positively correlated with bilirubin and AST levels. We conclude that circulating levels of interleukin-1 receptor antagonist and tumor necrosis factor soluble receptor may reflect ongoing disease activity and probably modulate some effects of endogenous interleukin-1 and tumor necrosis factor.