CO 2 -enhanced oil recovery (CO 2 -EOR) is a technique for commercially producing oil from depleted reservoirs by injecting CO 2 along with water. Because a large portion of the injected CO 2 remains in place, CO 2 -EOR is an option for permanently sequestering CO 2 . This study develops a generic integrated framework for optimizing CO 2 sequestration and enhanced oil recovery based on known parameter distributions for a depleted oil reservoir in Texas. The framework consists of a multiphase reservoir simulator coupled with geologic and statistical models. An integrated simulation of CO 2 − water−oil flow and reactive transport is conducted, followed by a global sensitivity and response surface analysis, for optimizing the CO 2 -EOR process. The results indicate that the reservoir permeability, porosity, thickness, and depth are the major intrinsic reservoir parameters that control net CO 2 injection/storage and oil/gas recovery rates. The distance between injection and production wells and the sequence of alternating CO 2 and water injection are the significant operational parameters for designing a five-spot CO 2 -EOR pattern that efficiently produces oil while storing CO 2 . The results from this study provide useful insights for understanding the potential and uncertainty of commercial-scale CO 2 sequestrations with a utilization component.