Plasma fibronectin (Fn), a 440-kD glycoprotein produced by hepatocytes, plays a role in nonspecific opsonization, "activation" of macrophage complement receptors, and hemostasis (1, 2) . The major source of Fn appears to be the liver, since hepatocyte production of Fn is adequate to account for the total circulating Fn pool (3). Theplasma concentration ofFn increases threeto fivefold during experimental inflammation, and hepatocytes isolated from animals harboring an inflammatory focus synthesize increased amounts of Fn (4). Thus, Fn appears to be an inducible acutephase protein (APP) in at least some species. Like other APPS, hepatocyte synthesis of Fn is stimulated by products contained in conditioned medium (CM) harvested from LPS-activated macrophages (5). Sera from inflamed animals and LPS-stimulated monocyte CM enhance hepatocyte Fn synthesis (5). A hepatocyte-stimulating factor (HSF) has been purified from these sources and found to be identical to IL-6 (6). Since IL-6 has been shown to regulate synthesis of many APPs (6), it seemed possible that IL-6 might also play a role in controlling Fn production . In this study, the stimulation of rat hepatocyte Fn production by monocyte CM, IL-1, TNF, and IL-6 was investigated . We report that IL-6 accounts for the total Fn-stimulating activity of monocyte CM, and of the three monokines, only IL-6 stimulates hepatocyte Fn production .