Purpose: Vascular endothelial dysfunction is well established in type 2 diabetes. Interleukin-12 (IL-12) and endoplasmic reticulum (ER) stress  are up-regulated in type  2  diabetic patients and  animal models of  type  2 diabetes.  However, the role and  underlying mechanisms of IL-12 and the ER stress CHOP in endothelial dysfunction are not fully understood.Methods: We generated double knockout mice between db−/db− and p40IL-12−/− mice (db−/db−p40-IL−12-/-) and endoplasmic (ER) stress-CHOP−/− mice (db−/db−CHOP-/-). We performed a glucose tolerance test (GTT) to determine the effect of IL-12 and ER stress CHOP on glucose metabolism. We assessed the endothelial function and determined the phosphorylation level of eNOS, Akt, AMPK, and the expression of ER stress (CHOP, BIP), and oxidative stress (Nox2 and Nox4 and NADPH oxidase activity).Results: The results showed that GTT was improved in db-/db−p40-IL−12-/- and db−/db−CHOP-/- suggesting IL-12 and CHOP as parts of a  mechanism  involved  in  the  development  of  type  2  diabetes.  The  microvascular  endothelial  dysfunction  in  db−/db− mouse  is associated  with  decreased  phosphorylated  eNOS,  Akt,  AMPK,  and  increased  CHOP,  BIP,  Nox2,  and  Nox4  expressions. Interestingly, disrupting IL-12 and ER stress CHOP in db−/db− mice significantly improved endothelial function, increased survival markers expression and decreased ER and oxidative stress.Conclusion: Using a genetic approach, these findings provide evidence that IL-12 and ER stress CHOP play a significant role in microvascular endothelial dysfunction in type 2 diabetes.