Impairment of the intestinal microcirculation (IMC) plays a critical role in the pathogenesis of sepsis. Consequently, the protection of the IMC represents a pivotal therapeutic target in severe sepsis. The aim of this study was to examine the effects of endocannabinoid system modulation on the IMC. Experimental animals groups were: control, endotoxemic animals (lipopolysaccharide; LPS), LPS + CB1R agonist, LPS + CB1R antagonist, LPS + CB1R agonist + CB1R antagonist, LPS + CB2R agonist, LPS + CB2R antagonist, LPS + CB2R agonist + CB2R antagonist, LPS + cannabinoid degradation enzyme inhibitor and LPS + enzyme inhibitor + CB2R antagonist. Endotoxemia significantly increased leukocyte adhesion in intestinal submucosal venules, and significantly reduced capillary perfusion of the muscular and mucosal layers of the intestinal wall. In acute experimental endotoxemia, IMC was significantly improved (by reducing leukocyte adhesion and increasing capillary perfusion) with CB1R inhibition or CB2R activation or inhibition of endocannabinoid degradation.