The production of transportation fuels from the conversion of biomass into gasoline and diesel in a bio-refinery is an attractive, clean, carbon neutral and sustainable process. The investment cost for the commercial application of a stand-alone bio-refinery may be reduced via integration with an existing petroleum refinery, whereby bio-refinery intermediates can be upgraded using the existing petroleum refinery infrastructure. In this work, two options of operational scenarios are studied and compared. The first option is to consider the bio-refinery and an existing petroleum refinery as stand-alone plants. The second option is to integrate bio-refinery network into an existing petroleum refinery and view it as an enterprise plant. The enterprise plant is represented in a superstructure, which is formulated as an MINLP (mixed integer nonlinear programming) model. The MINLP model involves logic constraints to allow the conditional designing of the optimal enterprise plant network. The model application is demonstrated on representative case studies. The model results shows that the optimal enterprise plant network design achieved 2.82 (21.5MM/year) higher profit compared to the combined profits of the stand-alone plants. As a result, the payback time for a new bio-refinery investment is reduced from 6.9 to 4.7 years. © 2013 Elsevier Ltd.