The injection of CO2 in exploited natural gas reservoirs as a means to reduce greenhouse gas (GHG) emissions is highly attractive as it takes place in well-known geological structures of proven integrity with respect to gas leakage. The injection of a reactive gas such as CO2 puts emphasis on the possible alteration of reservoir and caprock formations and especially of the wells' cement sheaths induced by the modification of chemical equilibria. Such studies are important for injectivity assurance, wellbore integrity, and risk assessment required for CO2 sequestration site qualification. Within a R&D project funded by Eni, we set up a numerical model to investigate the rock-cement alterations driven by the injection of CO2 into a depleted sweet natural gas pool. The simulations are performed with the TOUGHREACT simulator (Xu et al. in Comput Geosci 32:145-165, 2006) coupled to the TMGAS EOS module (Battistelli and Marcolini in Int J Greenh Gas Control 3:481-493, 2009) developed for the TOUGH2 family of reservoir simulators (Pruess et al. in TOUGH2 User's Guide, Version 2.0, 1999). On the basis of field data, the system is considered in isothermal (50A degrees C) and isobaric (128.5 bar) conditions. The effects of the evolving reservoir gas composition are taken into account before, during, and after CO2 injection. Fully water-saturated conditions were assumed for the cement sheath and caprock domains. The gas phase does not flow by advection from the reservoir into the interacting domains so that molecular diffusion in the aqueous phase is the most important process controlling the mass transport occurring in the system under study.