Portland cement can play a major role in providing cost-effective, long-term zonal isolation for CO2 capture and storage (CCS) used to mitigate climate change. However, achieving zonal isolation with Portland cement under supercritical CO2 environment for the required 1,000 year trapping period may be challenging. Some laboratory researchers report that Portland cement disintegrates when exposed to CO2, leading to potential leakage into the atmosphere or other to underground zones. Other researchers cite Portland cement samples from 30–50 year old CO2 EOR wells where sealing integrity was maintained, even though carbonation was found. In this paper we will discuss reasons likely for this disparity between research lab test results and actual well performance data. Carbonation of Portland cement is a thermodynamically favorable process and therefore difficult to avoid. But the effects can be minimized by various reactive chemical components optimized for the specific thermodynamic conditions. Our research shows partial carbonation of Portland cement is not detrimental unless the mechanical integrity is insufficient to provide effective zonal isolation. For these studies we have developed CO2 treatment test cells capable of producing conditions up to 200 °F and 2,000 psi. In addition, various analytical instruments including x-ray diffraction (XRD), thermo-gravimetric analysis (TGA) and mechanical properties measurement devices have been used for this study. In this paper we will discuss the importance of understanding the percentage of carbonation and depth of CO2 penetration, and how to control these factors by optimizing the cement blend. Interestingly, we found the amount of Portlandite { Ca(OH)2} that forms due to cement hydration and the cement-to-water ratio dictates the depth of penetration as well as percentage carbonation. The implications of this in relation to the long term chemical integrity of the cement sheath under downhole CCS conditions is discussed. This paper also includes the results of recent studies on the changes in mechanical properties of a properly optimized Portland cement blend for a period of up to one year. During this period, measurements were made at different time intervals to examine cement specimen treated with CO2 at 200 °F and 2,000 psi in the presence of water. The results show carbonation without any sign of loss of mechanical or sealing integrity that could lead to zonal isolation failure. Results from a separate set of experiments show the following: (1) Carbonation could be minimized by reducing the Portland cement content by adding Pozzolanic materials and by reducing the permeability and (2) Carbonation could help heal micro-cracks that may be caused by various well operations or ageing. However, such carbonation-induced healing is limited only to a certain width of cracks. In summary of this research, it is recommend that: (1) a high quality primary cement job be performed in adherence to all industry best practices; (2) the cement blend be properly optimized to minimize long-term CO2 corrosion; and (3) the sheath be designed for long-term mechanical integrity. This paper will discuss a comprehensive approach that may be taken to help ensure longer-term effective zonal isolation in new CO2 wells and remedial solutions for old wells and for plugging and abandoning wells.