In patients with systemic inflammatory response syndrome (SIRS), tolerance of peripheral blood mononuclear cells to a second challenge with lipopolysaccharide (LPS) has been described. Thoracic duct lymph transports LPS and represents the extravascular, interstitial fluid compartment of the body. The aim of this study was to determine the capacity of lymph to influence LPS-induced cytokine production in vitro. Thoracic duct lymph was obtained from patients with SIRS and without SIRS (controls). The effect of lymph and simultaneously collected plasma on LPS-induced cytokine production by normal peripheral blood mononuclear cells was assessed. Both lymph and plasma of patients with SIRS reduced LPS-induced tumor necrosis factor-alpha and interleukin-6 production (P < .01); lymph of controls also inhibited cytokine production (P < .01), although to a lesser extent. This study suggests that LPS tolerance may occur both in the intra- and extravascular compartments.