Studies on animal models have documented a role for the water-soluble protein fraction of mesenteric lymph as a conduit from hemorrhagic shock to acute lung injury and postinjury multiple organ failure. We hypothesize that mesenteric lymph is not an ultrafiltrate of plasma and contains specific protein mediators that may predispose patients to acute lung injury/multiple organ failure. Mesenteric lymph and plasma were collected from critically ill or injured patients and from nine patients with lymphatic injuries, during semielective spine reconstruction, or immediately before organ donation. Proteomic analyses were performed through immunoaffinity depletion of the 14 most abundant plasma proteins and 1D gel electrophoresis followed by liquid chromatography coupled online with mass spectrometry analyses. Overall, 548 proteins were identified in the patients undergoing semielective surgery, of which 155 were uniquely present in the lymph. In addition, the postshock plasma proteome was characterized by peculiar features, suggesting that only a partial overlap exists between the plasma and mesenteric lymph from trauma patients. Differential proteins between the matched plasma and mesenteric lymph from trauma patients could be related to coagulopathy and hypercoagulability, cell lysis, proinflammatory responses and immune system activation, extracellular matrix remodeling, lymph-specific immunomodulation and vascular hypoactivity/neoangiogenesis, and energy/redox metabolic adaptation to trauma. In conclusion, the proteome of mesenteric lymph is biologically different (in qualitative and quantitative terms) than that of a mere plasma ultrafiltrate.