Local and systemic inflammation has been implicated in the pathogenesis of acute pancreatitis and secondary multisystem organ failure. To assess the pro- and antiinflammatory response, the site of mediator production, and their route of diffusion, we sampled simultaneously ascites, thoracic lymph, and blood at the onset of end-organ dysfunction and for the following 6 days in 60 patients with acute pancreatitis. We used immunoassays to measure pro- and antiinflammatory cytokines and cell-based bioassays to assess the net pro- and antiinflammatory activity elicited by the biological fluids. Tumor necrosis factor-alpha and interleukin-1beta were detected in less than 15% of blood and lymph samples. Secondary pro- and antiinflammatory cytokines were found to be elevated early and throughout the sampling period in all compartments. Cytokine levels decreased from ascites to lymph to blood, suggesting a splanchnic origin. Prolonged diversion of ascites and lymph did not alter cytokine gradients, suggesting mediator transfer via the splanchnic blood circulation. Although a net proinflammatory activity ascribed to interleukin-1beta was detected in ascites, a net antiinflammatory activity was measured in virtually all lymph and blood samples, suggesting that the pancreas and the splanchnic area are sites of a proinflammatory response and that an early, dominant, and sustained antiinflammatory activity takes place in circulating compartments.