Background: Limited data exist regarding systemic inflammation and endotoxemia in different circulatory compartments in patients with acute variceal bleeding (AVB). Further, the correlation of these circulatory abnormalities with hepatic venous pressure gradient (HVPG) in AVB remain unexplored. Aim: To assess the circulatory milieu of peripheral and hepatic venous blood with regard to inflammation and endotoxemia and evaluated their correlation with HVPG in patients with AVB. Methods: In this prospective pilot study, serum interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), C-reactive protein (CRP), IgM anti-endotoxin antibody (indirect marker of endotoxemia) were evaluated simultaneously on day-2 of AVB in peripheral vein and hepatic vein at the time of HVPG estimation. Peripheral and hepatic venous circulatory milieu of different parameters was compared using scatter plots. Association of HVPG with parameters in different compartments was evaluated using spearman’s correlation. Results: Systemic circulatory cytokines, endotoxemia and HVPG were evaluated in 27 patients with AVB [mean age: 45.3±13 years, 66% males, mean MELD score: 15±4] with concomitant evaluation of hepatic venous components in a subset (n=16). On comparing hepatic and peripheral venous milieu, while IL-6 (r=0.53, P=0.034) and TNFα (r=0.55, P=0.03) correlated with each other in these compartments, endotoxemia (r=0.074, P=0.79), IL-1 (r=0.19, P=0.49) and CRP (R=0.18, P=0.51) did not. Peripheral venous IL-6 (r=0.71, P=0.001) correlated with HVPG whereas IL-1 (r=0.18, P=0.38), TNFα (r=0.33, P=0.097), CRP (R=0.021, P=0.92) and endotoxemia (r= -0.32, P=0.11) did not. None of the parameters in hepatic venous samples showed correlation with HVPG. Conclusions: The present study provides a proof-of concept of compartment specific pattern of systemic inflammation and endotoxemia in AVB. The association of peripheral but not hepatic venous IL-6 with HVPG suggests the role of systemic response to the event (AVB) as the source of inflammation and possibly a determinant of hepatic hemodynamics in AVB. Endotoxemia (both peripheral and hepatic venous) has a limited role in determining the hepatic hemodynamics in AVB.