Glucagon-like peptide-1 (GLP-1) is a proglucagon-derived hormone with cellular protective actions. We hypothesized that GLP-1 would protect the endothelium from injury during inflammation. Our aims were to determine the: (1) effect of GLP-1 on basal microvascular permeability, (2) effect of GLP-1 on increased microvascular permeability induced by lipopolysaccaride (LPS), (3) involvement of the GLP-1 receptor in GLP-1 activity, and (4) involvement of the cAMP/PKA pathway in GLP-1 activity. Microvascular permeability (L p ) of rat mesenteric post-capillary venules was measured in vivo. First, the effect of GLP-1 on basal L p was measured. Second, after systemic LPS injection, L p was measured after subsequent perfusion with GLP-1. Thirdly, L p was measured after LPS injection and perfusion with GLP-1+GLP-1 receptor antagonist. Lastly, L p was measured after LPS injection and perfusion with GLP-1+inhibitors of the cAMP/PKA pathway. Results are presented as mean area under the curve (AUC)±SEM. GLP-1 had no effect on L p (AUC: baseline=27±1.4, GLP-1=1±0.4, p=0.08). LPS increased L p two-fold (AUC: LPS=54±1.7, p<0.0001). GLP-1 reduced the LPS increase in L p by 75% (AUC: LPS+GLP-1=34±1.5, p<0.0001). GLP-1 antagonism reduced the effects of GLP-1 by 60% (AUC: LPS+GLP-1+antagonist=46±2.0, p<0.001). The cAMP synthesis inhibitor reduced the effects of GLP-1 by 60% (AUC: LPS+GLP-1+cAMP inhibitor=46±1.5, p<0.0001). The PKA inhibitor reduced the effects of GLP-1 by 100% (AUC: LPS+GLP-1+PKA inhibitor=56±1.5, p<0.0001). GLP-1 attenuates the increase in microvascular permeability induced by LPS. GLP-1 may protect the endothelium during inflammation, thus decreasing third-space fluid loss.