The study of natural analogues can inform the long-term performance security of engineered CO2 storage. There are natural CO2 reservoirs and CO2 seeps in Italy. Here, we study nine reservoirs and establish which are sealed or are leaking CO2 to surface. Their characteristics are compared to elucidate which conditions control CO2 leakage. All of the case studies would fail current CO2 storage site selection criteria, although only two leak CO2 to surface. The factors found to systematically affect seal performance are overburden geopressure and proximity to modern extensional faults. Amongst our case studies, the sealing reservoirs show elevated overburden geopressure whereas the leaking reservoirs do not. Since the leaking reservoirs are located within <10 km of modern extensional faults, pressure equilibration within the overburden may be facilitated by enhanced crustal permeability related to faulting. Modelling of the properties that could enable the observed CO2 leakage rates finds that high-permeability pathways (such as transmissive faults or fractures) become increasingly necessary to sustain leak rates as CO2 density decreases during ascent to surface, regardless of the leakage mechanism into the overburden. This work illustrates the value of characterizing the overburden geology during CO2 storage site selection to inform screening criterion, risk assessment and monitoring strategy.