Abstract: The effect of Vasoactive Intestinal Peptide (VIP) on Insulin Dependent Diabetes Mellitus (IDDM) and schistosomiasis together in combination has not been previously investigated. To assess its efficacy in such condition, VIP was administered to Schistosoma mansoni-infected streptozotocin-induced diabetic (ID) mice at a dose level of 41.6 ng kg–1 b.wt., 3 times/week, for 8 consecutive weeks starting from the 1st week of infection. The administration of VIP to ID mice induced a potential amelioration of serum glucose, insulin and C-peptide levels indicating the insulinogenic effect of this peptide. VIP also produced a significant decrease of hepatic granuloma volume and worm fecundity in the ID mice without affecting worm burden. The granuloma volume was found to be lower in the ID mice as compared to that of the infected non-diabetic ones. VIP administration produced marked decreases of the elevated liver collagen, serum carbohydrate antigen (CA.19.9) and liver alpha fetoprotein (AFP) content of ID mice as well as it succeeded, at least partially, to alleviate the altered liver enzyme activities. It also successfully increased the anti-inflammatory cytokine, IL-10 and decreased the elevated pro-inflammatory chemokines, IL-12 and TNF-α level in the serum of ID mice. These changes in cytokines explain the decrease in hepatic granuloma volume and reflect the anti-inflammatory effects of VIP. The increased oxidative stress markers and perturbed antioxidant defense system were profoundly improved in the ID mice treated with VIP. In conclusion, the VIP may have anti-hyperglycemic and insulinotropic effects, decrease liver and intestinal egg count and ameliorate liver pathologic deteriorations via its immunomodulatory effects on cytokines released from macrophages and T helper cells in addition to its improvement effect on the antioxidant defense system of the infected diabetic mice.