There are clinical data showing encouraging results for combining chemoradiotherapy with interferon (IFN)-alpha (CapRI scheme) for the treatment of pancreatic carcinoma. Here, it was tried to evaluate the antiangiogenic effect of IFN-alpha in combination with chemotherapy. Mice were inoculated with syngeneic pancreatic carcinoma cells in the pancreas. After 5 days, the animals were treated with 5-fluorouracil (5-FU)+/-IFN-alpha. Tumor growth, vascular endothelial growth factor (VEGF) serum levels and VEGF-R expression, real-time reverse transcription-polymerase chain reaction of mRNA coding for RGS-5, an angiogenic pericyte marker at sites of physiologic and pathologic angiogenesis and impact of IFN-alpha treatment on vessel density by CD31 stain and intravital microscopy were analyzed. The addition of IFN-alpha to 5-FU-treatment decreased tumor volume, reduced serum level of VEGF, and down-regulated the expression of VEGF-receptor significantly. Furthermore, the combination therapy revealed a decrease in vessel density and a down-regulation of RGS-5, which is a protein involved in angiogenic tumor vasculature. IFN-alpha significantly improves the outcome of 5-FU-therapy in treating pancreatic carcinoma. This is at least partly mediated by IFN-alpha antiangiogenic properties, which acts along with 5-FU on the VEGF system, vessel density, and RGS-5 expression in pericytes.