Due to the climate change and the strong dependence on fossil fuels, biomass-derived liquid transportation fuels and energy products have been proposed to deal with such situations. Usually, the prices of the bio-diesel and bio-gasoline are much higher than those of fossil fuels. The co-processing of bio-oil and vacuum gas oil (VGO) in a fluid catalytic cracker of a refinery has been proposed to utilize the existing refinery infrastructures and decrease the prices of bio-fuels. However, the integration between the bio-oil production and the existing refinery is not clear. In this work, a superstructure model is built to design and optimize the co-processing process with minimum total annual cost which features to select the optimal bio-oil production technology (fast pyrolysis or catalytic pyrolysis) and obtain the optimal integration scheme. Furthermore, the impacts of the prices of biomass and hydrogen, the bio-oil co-processing ratio on the economics of the co-processing system are also investigated. The optimal integration scheme of the co-processing of bio-oil and VGO can be obtained by solving the proposed model.